P13-kinases

ABSTRACT

New compounds of formula 1 are provided which by virtue of their pharmaceutical activity as PI3-kinase modulators may be used in the therapeutic field for the treatment of inflammatory or allergic diseases. 
     
       
         
         
             
             
         
       
     
     Examples of these include inflammatory and allergic respiratory complaints, inflammatory diseases of the gastro-intestinal tract and motor apparatus, inflammatory and allergic skin diseases, inflammatory eye diseases, diseases of the nasal mucosa, inflammatory or allergic conditions involving autoimmune reactions or inflammations of the kidney.

TECHNICAL FIELD

Phosphatidylinositol-3-kinases (PI3-kinases) are a subfamily of thelipid kinases which catalyse the transfer of a phosphate group to the3′-position of the inositol ring of phosphoinositides (Vanhaesebroeckand Waterfield, Exp Cell Res. 1999 Nov. 25; 253(1):239-54).

They have an important role in numerous cell processes such as e.g. cellgrowth and differentiation processes, the control of cytoskeletalchanges and the regulation of intracellular transport processes(Vanhaesebroeck et al., Annu Rev Biochem. 2001; 70:535-602). In view oftheir in vitro specificity for particular phosphoinositide substratesthe PI3-kinases may be divided into various classes. The members of thereceptor-regulated class I are heterodimeric enzymes which are made upof a catalytic subunit (p110) weighing 110-120 kDa and a non-catalyticsubunit (p50, p55, p85, p101) weighing 50-101 kDa. The most highlyconserved region in all the PI3-kinases is the C-terminally situatedkinase domain. It has structural features which can also be found in themajority of known protein kinases. These also include e.g. highlyconserved amino acids which are responsible for the coordination of theATP molecule (Walker et al., Nature. 1999 Nov. 18; 402(6759):313-20).

Three of the four members of the class I PI3-kinases associateconstitutively with an adaptor subunit weighing 50-85 kDa, of which p85is the prototype. The interaction takes place via the so-called p85binding domain which can be found on the catalytic subunits of thePI3-kinase α, β and δ. The three forms are grouped in class IA onaccount of this structural feature. The catalytic subunit γ of thePI3-kinase, p110γ, associates instead with a regulatory protein weighing101 kDa, which is known as p101. It constitutes Class IB of thePI3-kinases—of which it is currently the sole member. This structuraldivision into class IA and IB also shows parallels in the functionalproperties of the corresponding PI3-kinase isoforms (Vanhaesebroeck andWaterfield, Exp Cell Res. 1999 Nov. 25; 253(1):239-54)

Thus, the PI3-kinase α, β and δ are activated predominantly byreceptor-tyrosine-kinases (RTKs) or soluble tyrosine kinases. Thep85-subunit serves as an adaptor, as it is able to recognise and bindthe phosphorylated tyrosine groups of specific amino acid sequences(YxxM) with its SH2 domains. The PI3Kγ on the other hand is activatedmainly by Gβγ-subunits which are released from heterotrimeric G-proteinsafter activation of heptahelical receptors. This differing coupling tocell surface receptors combined with a more or less restrictiveexpression necessarily results in very different tasks and functions forthe 4 class I PI3-kinases in the intact organism (Wymann et al., TrendsPharmacol Sci. 2003 July; 24(7):366-76).

A number of independent findings would appear to indicate that class IAPI3-kinases are involved in uncontrolled cell growth and differentiationprocesses. Thus, the first detected PI3-kinase activity was associatedwith the transforming activity of viral oncogenes, such as e.g. themiddle T antigen of polyomaviruses, Src tyrosine kinases or activatedgrowth factors (Workman, Biochem Soc Trans. April; 32(Pt 2):393-6). Inmany tumours, such as e.g. breast cancer, ovarian or pancreaticcarcinoma, there is found to be an overactivity of Akt/PKB, which isactivated directly by the lipid products of class I PI3-kinases and thustransmits the signals on into the cell. Moreover, it was found justrecently that the PIK3CA-gene which codes for p110α has a high mutationfrequency in various types of tumour, such as colon, breast or lungcarcinomas, some examples of which were able to be characterised asactivating mutations (Samuels et al., Science. 2004 Apr. 23;304(5670):554).

The most recent member of the class IA PI3-kinases, PI3Kδ, is expressedmore restrictively than PI3Kα and β. In so-called “knock-in” mice inwhich the catalytic subunit of PI3Kδ, p110δ, had been replaced by aninactive mutant, it was demonstrated that this PI3K-isoenzyme plays aspecific part in the signal transmission of B- and T-lymphocytes afterantigen receptor stimulation (Okkenhaug et al., Science. 2002 August;297(5583):1031-4). These are mechanisms which play a part especially inautoimmune diseases such as e.g. Crohn's disease or rheumatoidarthritis.

The PI3Kγ is activated almost exclusively by G_(i)-coupling heptahelicalreceptors. Thus, in neutrophils in mice which express no PI3Kγ, noPI3,4,5-P₃ formation was observed if they were stimulated with IL-8,fMLP, LTB₄ or C5a (Hirsch et al., Science. 2000 Feb. 11;287(5455):1049-53). This shows that at least in this type of cell PI3Kγis the only PI3-kinase isoform which binds to these heptahelicalreceptors. Moreover, isolated neutrophils and macrophages from thePI3Kγ-deficient mice exhibited a sharply reduced chemotactic activity orproduction of oxygen radicals compared with a whole series of chemokinesand chemoattractors. Also reduced was the IgE-mediated activation ofmast cells which had been isolated from p110γ-deficient mice. There hasbeen some discussion that the mechanism responsible might be a positivefeedback mechanism in which the PI3Kγ is activated by G_(i)-couplingadenosine A₃ receptors (Laffargue et al., Immunity. 2002 March;16(3):441-51).

In spite of this decreased ability to react to inflammation mediators,the p110γ-deficient mice have normal viability and reproductive powersand have the same life expectancy as wild-type comparison animals rearedidentically. From this it can be concluded that the class IB PI3Kγ playsa central role in the activation of various inflammatory cells, andtherefore isoform-specific inhibitors represent an attractivepossibility for anti-inflammatory therapy with comparatively minor sideeffects (Ward and Finan, Curr Opin Pharmacol. 2003 August; 3(4):426-34).Apart from its function in leukocytes PI3Kγ also appears to be involvedin the cardiovascular system, despite its low expression incardiomyocytes. Thus, p110γ-deficient mice exhibited an increase incardiac muscle contractility which may presumably be explained by anoverproduction of cAMP (Crackower et al., Cell. 2002 Sep. 20;110(6):737-49). It has only recently been possible to demonstrate thatPI3Kγ is also involved in the development of cardiac hypertrophy. Thus,p110γ-deficient mice exhibited significantly reduced hypertrophy andfibrosis compared with wild-type animals in an isoproterenol-inducedcardiac insufficiency model (Oudit et al., Circulation. 2003 Oct. 28;108(17):2147-52).

The problem of the present invention was to provide new compounds whichby virtue of their pharmaceutical efficacy as PI3-kinase modulators maybe used in the therapeutic field for the treatment of inflammatory orallergic diseases. Examples which may be mentioned here includeinflammatory and allergic respiratory complaints, inflammatory diseasesof the gastrointestinal tract, rheumatoid arthritis, inflammatory andallergic skin diseases, inflammatory eye diseases, diseases of the nasalmucosa, inflammatory or allergic conditions involving autoimmunereactions, or inflammation of the kidneys.

PRIOR ART

PI3-kinase inhibitors for the treatment of inflammatory diseases areknown in the literature. Thus, WO 03/072557 discloses 5-phenylthiazolederivatives, WO 04/029055 discloses annelated azolopyrimidines and WO04/007491 discloses azolidinone-vinyl linked benzene derivatives.Moreover, the two specifications WO 04/052373 and WO 04/056820 disclosebenzoxazine into benzoxazin-3-one derivatives.

DETAILED DESCRIPTION OF THE INVENTION

Surprisingly it has been found that the above-mentioned problems aresolved by compounds of formula 1. Accordingly, the present inventionrelates to compounds of formula 1,

with the proviso that the circular line designated A denotes an aromaticsystem; wherein

-   Y denotes carbon, nitrogen atom, sulphur; preferably carbon,    nitrogen;-   Z denotes carbon, nitrogen atom, sulphur; preferably carbon,    nitrogen;-   j denotes 1, 2 or 3;-   k denotes 0 or 1;-   R^(a) denotes H, COR⁸, NR⁹R¹⁰, NO₂, OR⁸, SR¹¹, SOR¹¹, SO₂R¹¹,    NHCO—C₁₋₆-alkyl-NH₂, or a group selected from among C₁₋₆-alkyl,    C₂₋₆-alkenyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkenyl, C₁₋₆-Haloalkyl,    aryl, C₇₋₁₁-aralkyl, Spiro, het, heteroaryl and CH₂—O-aryl, which    may optionally be substituted;-   R⁸ denotes C₁₋₆-alkyl, C₃₋₆-cycloalkyl, NH₂, hetaryl or aryl,    optionally substituted by one or more halogens or C₁₋₄-alkyl;-   R⁹ denotes H, COOR¹², CONR¹² or C₁₋₆-alkyl, optionally substituted    by one or more COOH, N(C₁₋₆-alkyl)₂ or het, optionally substituted    by one or more C₁₋₆-alkyl; or R⁹ denotes het, optionally substituted    by one or more C₁₋₄-alkyl;-   R¹⁰ denotes H, C₁₋₆-alkyl, CO—C₁₋₆-alkyl or C₂₋₆-alkynyl;-   R¹¹ denotes C₁₋₆-alkyl, optionally substituted by one or more    N(C₁₋₄-alkyl)₂;-   R^(b) denotes R⁴, OR⁴, —CH₂OR⁴, COR⁴, COOR⁴, CONR⁴R⁵, NR⁴R⁵,    NR⁵COR⁴, NR⁵COOR⁴, NR⁵CONR⁴R⁵, NR⁵SOR⁴ or NR⁵SO₂R⁴;-   R⁴, R⁵ denote H, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkylene-OH,    C₂₋₆-alkenyl, C₇₋₁₁-aralkyl, C₂₋₄-alkenyl-aryl, C₂₋₄-alkynyl-aryl,    C₁₋₄-alkyl-hetaryl, C₂₋₄-alkenyl-hetaryl, C₂₋₄-alkynyl-hetaryl,    C₂₋₆-alkynyl, optionally substituted by Si(C₁₋₄-alkyl)₃, or R⁴    denotes a group selected from among aryl, het, hetaryl and    optionally substituted by C₁₋₄-alkyl;    or R⁴ and R⁵ together form a five-, six- or seven-membered ring    consisting of carbon atoms and optionally a heteroatom selected from    among oxygen, nitrogen and sulphur;-   R^(c) denotes NHR⁶ or a group selected from among

wherein

-   B denotes a bond, C₁₋₆-alkyl, C₂₋₆-alkenyl or C₂₋₆-alkynyl;-   R⁶ denotes H or a group selected from among C₁₋₄-alkyl,    C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkenyl, het,    aryl, hetaryl optionally substituted by one or more groups R^(6.1);    -   R^(6.1) denotes halogen, CF₃, OH, CN, OMe, SO₂(C₁₋₄-alkyl);-   R⁷ denotes H, C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl,    C₃₋₆-cycloalkyl, NR^(7.1)R^(7.2), OR^(7.2), SR^(7.2), hetaryl, het,    optionally substituted by C₁₋₄-alkyl or CONH₂;    -   R^(7.1) denotes H, C₁₋₆-alkyl, (CH₂)₂₋₄R^(7.1.1) or COObutyl;    -   R^(7.2) denotes H, C₁₋₆-alkyl, optionally substituted by one or        more OH;        -   R^(7.1.1) denotes NR^(7.1.1.1)R^(7.1.1.2), het or            1-imidazolyl, 2-(N-ethylpyrrolidine);            -   R^(7.1.1.1) denotes H or C₁₋₆-alkyl;            -   R^(7.1.1.2) denotes H or C₁₋₆-alkyl;                and the pharmacologically acceptable salts,                diastereomers, enantiomers, racemates, hydrates or                solvates thereof, with the proviso that R^(a) cannot be                H or Me if Y=nitrogen; Z=nitrogen; j=2; k=0; R^(b)=H and                R^(c)=NHCONH-Et.

Preferred compounds of formula 1 mentioned above are those wherein

-   R^(a) denotes a group selected from among aryl, C₇₋₁₁-aralkyl and    heteroaryl, which may optionally be substituted by one or more    groups selected from among R¹, R² and R³;-   R¹ and R² independently of one another denote C₁₋₆-alkyl,    C₂₋₆-alkenyl C₂₋₆-alkynyl, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkenyl,    C₁₋₆-haloalkyl, C₁₋₆-alkylene-COOH, C₁₋₆-alkoxy, halogen, OH, CN,    COR^(1.1), O—C₁₋₄-haloalkyl, NO₂ or SR^(1.1), SOR^(1.1), SO₂R^(1.1),    het or hetaryl,    -   R^(1.1) denotes OH, C₁₋₆-alkyl, C₂₋₆-alkenyl C₂₋₆-alkynyl,        NR^(1.1.1)R^(1.1.2)        -   R^(1.1.1) denotes H, C₁₋₆-alkyl, optionally substituted by a            group selected from among NH₂, NHMe, NMe₂;        -   R^(1.1.2) denotes H, C₁₋₆-alkyl;        -   or R^(1.1.1) and R^(1.1.2) together form a five- or            six-membered heterocyclic ring, which may optionally be            substituted by a group selected from among methyl, ethyl,            propyl;-   R³ denotes a group selected from among

-   -   wherein    -   X denotes a bond or C₁₋₄-alkylene;    -   X′ denotes C₁₋₄-alkylene, C₂₋₄-alkenylene or C₁₋₄-alkynylene    -   R^(3a) denotes a group, which may be identical or different,        selected from among R^(3.1), R^(3.2) and R^(3.3)    -   R^(3.1) denotes spiro or het, while het may optionally be        substituted by one or more R^(3.1.1);        -   R^(3.1.1) denotes C₁₋₆-alkyl, C₂₋₆-alkenyl, OH,            C₁₋₄-alkylene-OH, C₁₋₄-alkylene-NR^(3.1.1.1)R^(3.1.1.2),            COR^(3.1.1.1), COOR^(3.1.1.1), CONR^(3.1.1.1)R^(3.1.1.2),            NR^(3.1.1.1)R^(3.1.1.2), het, hetaryl, NHCOR^(3.1.1.1)            -   R^(3.1.1.1) denotes a group selected from among H,                C₁₋₄-alkyl, aryl and C₇₋₁₁-aralkyl; optionally                substituted by a group selected from among halogen, OH                and CN;            -   R^(3.1.1.2) denotes H, C₁₋₄-alkyl;    -   R^(3.2) denotes a group selected from among C₃₋₆-cycloalkyl,        het, hetaryl and spiro which is optionally substituted by one or        more R^(3.2.1)        -   R^(3.2.1) denotes C₁₋₆-alkyl, C₃₋₆-cycloalkyl, OH,            NR^(3.2.1.1)R^(3.2.1.2), NHCOR^(3.2.1.3) or het, optionally            substituted by one or more groups selected from among            C₁₋₄-alkyl, SO₂R^(3.2.1.1), CH₂—C₃₋₆-cycloalkyl and aryl;            -   R^(3.2.1.1) denotes H, C₁₋₄-alkyl or C₇₋₁₁- aralkyl;            -   R^(3.2.1.2) denotes H, C₁₋₄-alkyl or C₇₋₁₁- aralkyl;            -   R^(3.2.1.3) denotes aryl, C₇₋₁₁-aralkyl; or        -   C₁₋₆-alkyl, which is optionally substituted by one or two            R^(3.2.2);        -   R^(3.2.2) denotes C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,            COOR^(3.2.2.1), CONR^(3.2.2.1)R^(3.2.2.2),            NR^(3.2.2.1)R^(3.2.2.2), NHCOR^(3.2.2.1), C₁₋₆-haloalkyl,            CN, OR^(3.2.2.1), SO₂R^(3.2.2.1), C₃₋₆-cycloalkyl, CO-het,            C₂₋₄-alkynyl-hetaryl, guanidine or a group selected from            among het, hetaryl and aryl, which is optionally substituted            by one or more groups selected from among halogen,            C₁₋₆-alkyl, CONR^(3.2.2.1)R^(3.2.2.2), OH, imidazolidinone;            -   R^(3.2.2.1) denotes H or C₁₋₆-alkyl, aryl, C₇₋₁₁-aralkyl            -   R^(3.2.2.2) denotes H or C₁₋₆-alkyl; or        -   aryl, which is optionally substituted by one or two            R^(3.2.3)        -   R^(3.2.3) denotes a group selected from among            NH—C₁₋₆-alkyl-N(C₁₋₆-alkyl)₂ or het, while het may            optionally be substituted by a C₁₋₆-alkyl group;    -   R^(3.3) denotes H or a group selected from among C₁₋₆-alkyl,        C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-haloalkyl and aryl, which may        optionally be substituted by one or more groups R^(3.3.1);        -   R^(3.3.1) denotes C₃₋₆-cycloalkyl, C₃₋₆-cycloalkenyl,            OR^(3.3.1.1), NR^(3.3.1.1)R^(3.3.1.2),            CONR^(3.3.1.1)R^(3.3.1.2), COOR^(3.3.1.1),            NR^(3.3.1.1)COR^(3.3.1.2), SOR^(3.3.1.1), SO₂R^(3.3.1.1),            C(NR^(3.3.1.1)R^(3.3.1.2))NR^(3.3.1.3),            NR^(3.3.1.1)CONR^(3.3.1.2)R^(3.3.1.3), OH, CN, halogen or            het, optionally substituted by one or more groups selected            from among C₁₋₄-alkyl, SO₂H, SO₂—C₁₋₄-alkyl,            SO₂C₇₋₁₁-aralkyl, CH₂—C₃₋₆-cycloalkyl and aryl;            -   R^(3.3.1.1), R^(3.3.1.2) and R^(3.3.1.3) denote a group                selected from among C₁₋₆-alkyl, C₂₋₆-alkenyl,                C₂₋₆-alkynyl, C₇₋₁₁-aralkyl, C₂₋₄-alkenyl-aryl,                C₂₋₄-alkynyl-aryl, C₁₋₄-alkyl-hetaryl,                C₂₋₄-alkenyl-hetaryl, C₂₋₄-alkynyl-hetaryl,                COC₁₋₄-alkyl-hetaryl, COC₂₋₄-alkenyl-hetaryl,                COC₂₋₄-alkynyl-hetaryl; or            -   two of the groups R^(3.3.1.1), R^(3.3.1.2) and                R^(3.3.1.3) together form a ring, consisting of carbon                atoms and optionally a heteroatom selected from among                oxygen, nitrogen and sulphur;

-   R^(a) denotes H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₈-cycloalkyl,    C₃₋₈-cycloalkenyl, C₁₋₆-haloalkyl, COR⁸, NR⁹R¹⁰, NO₂, OR⁸, SR¹¹,    SOR¹¹, SO₂R¹¹, NHCO—C₁₋₆-alkyl-NH₂, spiro or a group selected from    among C₇₋₁₁- aralkyl, CH₂—O-aryl and het which may optionally be    substituted by one or more halogens, C₁₋₆-alkyl, CO—C₁₋₄-haloalkyl,    C₁₋₄-alkyl-NH₂ or CH₂NHCOOR¹²;

-   R⁸ denotes C₁₋₆-alkyl, C₃₋₆-cycloalkyl, NH₂, hetaryl or aryl,    optionally substituted by one or more halogens or C₁₋₄-alkyl;

-   R⁹ denotes H, COOR¹², CONR¹² or C₁₋₆-alkyl, optionally substituted    by one or more COOH, N(C₁₋₆-alkyl)₂ or het, optionally substituted    by one or more C₁₋₆-alkyl; or R⁹ denotes het, optionally substituted    by one or more C₁₋₄-alkyl;

-   R¹⁰ denotes H, C₁₋₆-alkyl, CO—C₁₋₆-alkyl or C₂₋₆-alkynyl;

-   R¹¹ denotes C₁₋₆-alkyl, optionally substituted by one or more    N(C₁₋₄-alkyl)₂;

-   R¹² denotes H, C₁₋₆-alkyl;    and the pharmacologically acceptable salts, diastereomers,    enantiomers, racemates, hydrates or solvates thereof, with the    proviso that R^(a) cannot be H or Me if Y=nitrogen; Z=nitrogen; j=2;    k=0; R^(b)=H and R^(c)=NHCONH-Et.

Preferred compounds of formula 1 mentioned above are those wherein

-   R^(a) denotes a group selected from among aryl, C₇₋₁₁-aralkyl and    hetaryl, which may optionally be substituted by one or more groups    selected from among R¹, R² and R³;-   R¹ and R² independently of one another denote C₁₋₆-alkyl,    C₂₋₆-alkenyl C₂₋₆-alkynyl, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkenyl,    C₁₋₆-haloalkyl, C₁₋₆-alkylene-COOH, C₁₋₆-alkoxy, halogen, OH, CN,    COR^(1.1), O—C₁₋₄-haloalkyl, NO₂ or SR^(1.1), SOR^(1.1), SO₂R^(1.1),    het or hetaryl,    -   R^(1.1) denotes OH, C₁₋₆-alkyl, C₂₋₆-alkenyl C₂₋₆-alkynyl,        NR^(1.1.1)R^(1.1.2)        -   R^(1.1.1) denotes H, C₁₋₆-alkyl, optionally substituted by a            group selected from among NH₂, NHMe, NMe₂;        -   R^(1.1.2) denotes H, C₁₋₆-alkyl;        -   or R^(1.1.1) and R^(1.1.2) together form a five- or            six-membered heterocyclic ring, which may optionally be            substituted by a group selected from among methyl, ethyl,            propyl;-   R³ denotes a group selected from among

-   -   wherein    -   X denotes a bond or C₁₋₄-alkylene;    -   R^(3a) denotes a group, which may be identical or different,        selected from among R^(3.1), R^(3.2) and R^(3.3)    -   R^(3.1) denotes spiro or het, while het may optionally be        substituted by one or more R^(3.11)        -   R^(3.1.1) denotes C₁₋₆-alkyl, C₂₋₆-alkenyl, OH,            C₁₋₄-alkylene-OH, C₁₋₄-alkylene-NR^(3.1.1.1)R^(3.1.1.2),            COR^(3.1.11), COOR^(3.1.1.1), CONR^(3.1.1.1)R^(3.1.1.2),            NR^(3.1.1.1)R^(3.1.1.2), het, hetaryl, NHCOR^(3.1.1.1)            -   R^(3.1.1.1) denotes a group selected from among H,                C₁₋₄-alkyl, aryl and C₇₋₁₁-aralkyl; optionally                substituted by a group selected from among halogen, OH                and CN;            -   R^(3.1.1.2) denotes H, C₁₋₄-alkyl;    -   R^(3.2) denotes a group selected from among C₃₋₆-cycloalkyl,        het, hetaryl and spiro which is optionally substituted by one or        more R^(3.2.1)        -   R^(3.2.1) denotes C₁₋₆-alkyl, C₃₋₆-cycloalkyl, OH,            NR^(3.2.1.1)R^(3.2.1.2), NHCOR^(3.2.1.3) or het, optionally            substituted by one or more groups selected from among            C₁₋₄-alkyl, SO₂R^(3.2.1.1), CH₂—C₃₋₆-cycloalkyl and aryl;            -   R^(3.2.1.1) denotes H, C₁₋₄-alkyl or C₇₋₁₁- aralkyl;            -   R^(3.2.1.2) denotes H, C₁₋₄-alkyl or C₇₋₁₁- aralkyl;            -   R^(3.2.1.3) denotes aryl, C₇₋₁₁-aralkyl; or        -   C₁₋₆-alkyl, which is optionally substituted by one or two            R^(3.2.2);        -   R^(3.2.2) denotes C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,            COOR^(3.2.2.1) CONR^(3.2.2.1)R^(3.2.2.2),            NR^(3.2.2.1)R^(3.2.2.2), NHCOR^(3.2.2.1), C₁₋₆-haloalkyl,            CN, OR^(3.2.2.1), SO₂R^(3.2.2.1), C₃₋₆-cycloalkyl, CO-het,            C₂₋₄-alkynyl-hetaryl, guanidine or a group selected from            among het, hetaryl and aryl, which is optionally substituted            by one or more groups selected from among halogen,            C₁₋₆-alkyl, CONR^(3.2.2.1)R^(3.2.2.2), OH, imidazolidinone;            -   R^(3.2.2.1) denotes H or C₁₋₆-alkyl, aryl, C₇₋₁₁-aralkyl            -   R^(3.2.2.2) denotes H or C₁₋₆-alkyl; or        -   aryl, which is optionally substituted by one or two            R^(3.2.3) R^(3.2.3) denotes a group selected from among            NH—C₁₋₆-alkyl-N(C₁₋₆-alkyl)₂ or het, while het may            optionally be substituted by a C₁₋₆-alkyl group;    -   R^(3.3) denotes H or a group selected from among C₁₋₆-alkyl,        C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-haloalkyl and aryl, which may        optionally be substituted by one or more groups R^(3.3.1);        -   R^(3.3.1) denotes C₃₋₆-cycloalkyl, C₃₋₆-cycloalkenyl,            OR^(3.3.1.1), NR^(3.3.1.1)R^(3.3.1.2),            CONR^(3.3.1.1)R^(3.3.1.2), COOR^(3.3.1.1),            NR^(3.3.1.1)COR^(3.3.1.2), SOR^(3.3.1.1), SO₂R^(3.3.1.1),            C(NR^(3.3.1.1)R^(3.3.1.2))NR^(3.3.1.3),            NR^(3.3.1.1)CONR^(3.3.1.2)R^(3.3.1.3), OH, CN, halogen or            het, optionally substituted by one or more groups selected            from among C₁₋₄-alkyl, SO₂H, SO₂—C₁₋₄-alkyl,            SO₂C₇₋₁₁-aralkyl, CH₂—C₃₋₆-cycloalkyl and aryl;            -   R^(3.3.1.1), R^(3.3.1.2) and R^(3.3.1.3) denote a group                selected from among C₁₋₆-alkyl, C₂₋₆-alkenyl,                C₂₋₆-alkynyl, C₇₋₁₁-aralkyl, C₂₋₄-alkenyl-aryl,                C₂₋₄-alkynyl-aryl, C₁₋₄-alkyl-hetaryl,                C₂₋₄-alkenyl-hetaryl, C₂₋₄-alkynyl-hetaryl,                COC₁₋₄-alkyl-hetaryl, COC₂₋₄-alkenyl-hetaryl,                COC₂₋₄-alkynyl-hetaryl, or            -   two of the groups R^(3.3.1.1), R^(3.3.1.2) and                R^(3.3.1.3) together form a ring, consisting of carbon                atoms and optionally a heteroatom selected from among                oxygen, nitrogen and sulphur;

-   R^(a) denotes H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₈-cycloalkyl,    C₃₋₈-cycloalkenyl, C₁₋₆-haloalkyl, COR⁸, NR⁹R¹⁰, NO₂, OR⁸, SR¹¹,    SOR¹¹, SO₂R¹¹, NHCO—C₁₋₆-alkyl-NH₂, spiro or a group selected from    among C₇₋₁₁- aralkyl, CH₂—O-aryl and het which may optionally be    substituted by one or more halogens, C₁₋₆-alkyl, CO—C₁₋₄-haloalkyl,    C₁₋₄-alkyl-NH₂ or CH₂NHCOOR¹²;

-   R⁸ denotes C₁₋₆-alkyl, C₃₋₆-cycloalkyl, NH₂, hetaryl or aryl,    optionally substituted by one or more halogens or C₁₋₄-alkyl;

-   R⁹ denotes H, COOR¹², CONR¹² or C₁₋₆-alkyl, optionally substituted    by one or more COOH, N(C₁₋₆-alkyl)₂ or het, optionally substituted    by one or more C₁₋₆-alkyl; or R⁹ denotes het, optionally substituted    by one or more C₁₋₄-alkyl;

-   R¹⁰ denotes H, C₁₋₆-alkyl, CO—C₁₋₆-alkyl or C₂₋₆-alkynyl;

-   R¹¹ denotes C₁₋₆-alkyl, optionally substituted by one or more    N(C₁₋₄-alkyl)₂;

-   R¹² denotes H, C₁₋₆-alkyl;    and the pharmacologically acceptable salts, diastereomers,    enantiomers, racemates, hydrates or solvates thereof, with the    proviso that R^(a) cannot be H or Me if Y=nitrogen; Z=nitrogen; j=2;    k=0; R^(b)=H and R^(c)=NHCONH-Et.

Preferred compounds of formula 1 mentioned above are those wherein

-   R^(a) denotes a group selected from among aryl, C₇₋₁₁-aralkyl and    hetaryl, which may optionally be substituted by one or more groups    selected from among R¹, R² and R³;-   R¹ and R² independently of one another denote C₁₋₆-alkyl,    C₂₋₆-alkenyl C₂₋₆-alkynyl, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkenyl,    C₁₋₆-haloalkyl, C₁₋₆-alkylene-COOH, C₁₋₆-alkoxy, halogen, OH, CN,    COR^(1.1), O—C₁₋₄-haloalkyl, NO₂ or SR^(1.1), SOR^(1.1), SO₂R^(1.1),    het or hetaryl,    -   R^(1.1) denotes OH, C₁₋₆-alkyl, C₂₋₆-alkenyl C₂₋₆-alkynyl,        NR^(1.1.1)R^(1.1.2)        -   R^(1.1.1) denotes H, C₁₋₆-alkyl, optionally substituted by a            group selected from among NH₂, NHMe, NMe₂;        -   R^(1.1.2) denotes H, C₁₋₆-alkyl;        -   or R^(1.1.1) and R^(1.1.2) together form a five- or            six-membered heterocyclic ring, which may optionally be            substituted by a group selected from among methyl, ethyl,            propyl;-   R³ denotes a group selected from among

-   -   wherein    -   X denotes a bond or C₁₋₄-alkylene;    -   R^(3a) denotes a group, which may be identical or different,        selected from among R^(3.1), R^(3.2) and R^(3.3);    -   R^(3.1) denotes spiro or het, while het may optionally be        substituted by one or more R^(3.1.1);        -   R^(3.1.1) denotes C₁₋₆-alkyl, C₂₋₆-alkenyl, OH,            C₁₋₄-alkylene-OH, C₁₋₄-alkylene-NR^(3.1.1.1)R^(3.1.1.2),            COR^(3.1.1.1), COOR^(3.1.1.1), CONR^(3.1.1.1)R^(3.1.1.2),            NR^(3.1.1.1)R^(3.1.1.2), het, hetaryl, NHCOR^(3.1.1.1)            -   R^(3.1.1.1) denotes a group selected from among H,                C₁₋₄-alkyl, aryl and C₇₋₁₁-aralkyl; optionally                substituted by a group selected from among halogen, OH                and CN;            -   R^(3.1.1.2) denotes H, C₁₋₄-alkyl;        -   R^(3.2) denotes a group selected from among C₃₋₆-cycloalkyl,            het, hetaryl and spiro which is optionally substituted by            one or more R^(3.2.1)            -   R^(3.2.1) denotes C₁₋₆-alkyl, C₃₋₆-cycloalkyl, OH,                —NR^(3.2.1.1)R^(3.2.1.2) NHCOR^(3.2.1.3) or het,                optionally substituted by one or more groups selected                from among C₁₋₄-alkyl, SO₂R^(3.2.1.1),                CH₂—C₃₋₆-cycloalkyl and aryl;            -   R^(3.2.1.1) denotes H, C₁₋₄-alkyl or C₇₋₁₁- aralkyl;            -   R^(3.2.1.2) denotes H, C₁₋₄-alkyl or C₇₋₁₁- aralkyl;            -   R^(3.2.1.3) denotes aryl, C₇₋₁₁-aralkyl; or        -   —C₁₋₆-alkyl, which is optionally substituted by one or two            R^(3.2.2);        -   R^(3.2.2) denotes C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,            COOR^(3.2.2.1), CONR^(3.2.2.1)R^(3.2.2.2),            NR^(3.2.2.1)R^(3.2.2.2), NHCOR^(3.2.2.1), C₁₋₆-haloalkyl,            CN, OR^(3.2.2.1), SO₂R^(3.2.2.1), C₃₋₆-cycloalkyl, CO-het,            C₂₋₄-alkynyl-hetaryl, guanidine or a group selected from            among het, hetaryl and aryl, which is optionally substituted            by one or more groups selected from among halogen,            C₁₋₆-alkyl, CONR^(3.2.2.1)R^(3.2.2.2), OH, imidazolidinone;            -   R^(3.2.2.1) denotes H or C₁₋₆-alkyl, aryl, C₇₋₁₁-aralkyl            -   R^(3.2.2.2) denotes H or C₁₋₆-alkyl; or        -   aryl, which is optionally substituted by one or two            R^(3.2.3)        -   R^(3.2.3) denotes a group selected from among            NH—C₁₋₆-alkyl-N(C₁₋₆-alkyl)₂ or het, while het may            optionally be substituted by a C₁₋₆-alkyl group;    -   R^(3.3) denotes H or a group selected from among C₁₋₆-alkyl,        C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₁₋₄-haloalkyl and aryl, which may        optionally be substituted by one or more groups R^(3.3.1);        -   R^(3.3.1) denotes C₅₋₆-cycloalkyl, C₅₋₆-cycloalkenyl,            OR^(3.3.1.1), NR^(3.3.1.1)R^(3.3.1.2),            CONR^(3.3.1.1)R^(3.3.1.2), COOR^(3.3.1.1),            NR^(3.3.1.1)COR^(3.3.1.2), SOR^(3.3.1.1), SO₂R^(3.3.1.1),            C(NR^(3.3.1.1)R^(3.3.1.2))NR^(3.3.1.3),            NR^(3.3.1.1)CONR^(3.3.1.2)R^(3.3.1.3), OH, CN, halogen or            het, optionally substituted by one or more groups selected            from among C₁₋₄-alkyl, SO₂H, SO₂—C₁₋₄-alkyl,            SO₂C₇₋₁₁-aralkyl, CH₂—C₃₋₆-cycloalkyl and aryl;            -   R^(3.3.1.1), R^(3.3.1.2) and R^(3.3.1.3) denote a group                selected from among C₁₋₄-alkyl, C₂₋₄-alkenyl,                C₂₋₄-alkynyl, C₇₋₁₁-aralkyl, C₂₋₄-alkenyl-aryl,                C₂₋₄-alkynyl-aryl, C₁₋₄-alkyl-hetaryl,                C₂₋₄-alkenyl-hetaryl, C₂₋₄-alkynyl-hetaryl,                COC₁₋₄-alkyl-hetaryl, COC₂₋₄-alkenyl-hetaryl,                COC₂₋₄-alkynyl-hetaryl; or            -   two of the groups R^(3.3.1.1), R^(3.3.1.2) and                R^(3.3.1.3) together form a five-, six- or                seven-membered ring, consisting of carbon atoms and                optionally a heteroatom selected from among oxygen,                nitrogen and sulphur;

-   R^(a) denotes H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₈-cycloalkyl,    C₃₋₈-cycloalkenyl, C₁₋₆-haloalkyl, COR⁸, NR⁹R¹⁰, NO₂, OR⁸, SR¹¹,    SOR¹¹, SO₂R¹¹, NHCO—C₁₋₆-alkyl-NH₂, spiro or a group selected from    among C₇₋₁₁- aralkyl, CH₂—O-aryl and het which may optionally be    substituted by one or more halogens, C₁₋₆-alkyl, CO—C₁₋₄-haloalkyl,    C₁₋₄-alkyl-NH₂ or CH₂NHCOOR¹²;

-   R⁸ denotes C₁₋₆-alkyl, C₃₋₆-cycloalkyl, NH₂, hetaryl or aryl,    optionally substituted by one or more halogens or C₁₋₄-alkyl;

-   R⁹ denotes H, COOR¹² or C₁₋₄-alkyl, optionally substituted by one or    more COOH, N(C₁₋₄-alkyl)₂ or het, optionally substituted by one or    more C₁₋₄-alkyl; or R⁹ denotes het, optionally substituted by one or    more C₁₋₄-alkyl;

-   R¹⁰ denotes H, C₁₋₆-alkyl, CO—C₁₋₄-alkyl or C₂₋₆-alkynyl;

-   R¹¹ denotes C₁₋₆-alkyl, optionally substituted by one or more    N(C₁₋₄-alkyl)₂;

-   R¹² denotes C₁₋₆-alkyl;

-   R^(b) denotes R⁴, OR⁴, —CH₂OR⁴, COR⁴, COOR⁴, CONR⁴R⁵, NR⁴R⁵,    NR⁵COR⁴, NR⁵COOR⁴, NR⁵CONR⁴R⁵, NR⁵SOR⁴ or NR⁵SO₂R⁴;

-   R⁴ denotes H, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkylene-OH,    C₂₋₆-alkenyl, C₇₋₁₁-aralkyl, C₂₋₄-alkenyl-aryl, C₂₋₄-alkynyl-aryl,    C₁₋₄-alkyl-hetaryl, C₂₋₄-alkenyl-hetaryl, C₂₋₄-alkynyl-hetaryl,    C₂₋₆-alkynyl, optionally substituted by Si(C₁₋₄-alkyl)₃, or R⁴    denotes a group selected from among aryl, het, hetaryl and    optionally substituted by C₁₋₄-alkyl;

-   R⁵ denotes H or C₁₋₆-alkyl;    or R⁴ and R⁵ together form a five-, six- or seven-membered ring    consisting of carbon atoms and optionally a heteroatom selected from    among oxygen, nitrogen and sulphur;

R^(c) denotes NHR⁶ or a group selected from among

wherein

-   B denotes a bond, C₁₋₄-alkyl or C₂₋₄-alkynyl;-   R⁶ denotes H or a group selected from among C₁₋₄-alkyl,    C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkenyl, het,    aryl, hetaryl optionally substituted by one or more groups R^(6.1;)    -   R^(6.1) denotes halogen, CF₃, OH, CN, OMe, SO₂(C₁₋₄-alkyl);-   R⁷ denotes H, C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl,    C₃₋₆-cycloalkyl, NR^(7.1)R^(7.2), OR^(7.2), SR^(7.2), hetaryl, het,    optionally substituted by C₁₋₄-alkyl or CONH₂;    -   R^(7.1) denotes H, C₁₋₄-alkyl, (CH₂)₂₋₄R^(7.1.1) or COObutyl;    -   R^(7.2) denotes H, C₁₋₆-alkyl, optionally substituted by one or        more OH;        -   R^(7.1.1) denotes NR^(7.1.1.1)R^(7.1.1.2), het or            1-imidazolyl, 2-(N-ethylpyrrolidine);            -   R^(7.1.1.1) denotes H or C₁₋₆-alkyl;            -   R^(7.1.1.2) denotes H or C₁₋₆-alkyl;                and the pharmacologically acceptable salts,                diastereomers, enantiomers, racemates, hydrates or                solvates thereof, with the proviso that R^(a) cannot be                H or Me if Y=nitrogen; Z=nitrogen; j=2; k=0; R^(b)=H and                R^(c)=NHCONH-Et. Preferred compounds of formula 1                mentioned above are those wherein-   R^(a) denotes a group selected from among aryl, C₇₋₁₁-aralkyl and    hetaryl, which may optionally be substituted by one or more groups    selected from among R¹, R² and R³;-   R¹ and R² independently of one another denote C₁₋₆-alkyl,    C₂₋₆-alkenyl C₂₋₆-alkynyl, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkenyl,    C₁₋₆-haloalkyl, C₁₋₆-alkylene-COOH, C₁₋₆-alkoxy, halogen, OH, CN,    COR^(1.1), O—C₁₋₄-haloalkyl, NO₂ or SR^(1.1), SOR^(1.1), SO₂R^(1.1),    het or hetaryl,    -   R^(1.1) denotes OH, C₁₋₆-alkyl, C₂₋₆-alkenyl C₂₋₆-alkynyl,        NR^(1.1.1)R^(1.1.2)        -   R^(1.1.1) denotes H, C₁₋₆-alkyl, optionally substituted by a            group selected from among NH₂, NHMe, NMe₂;        -   R^(1.1.2) denotes H, C₁₋₆-alkyl;        -   or R^(1.1.1) and R^(1.1.2) together form a five- or            six-membered heterocyclic ring, which may optionally be            substituted by a group selected from among methyl, ethyl,            propyl;-   R³ denotes a group selected from among

-   -   wherein    -   X denotes a bond or C₁₋₄-alkylene;    -   R^(3a) denotes a group, which may be identical or different,        selected from among R^(3.1), R^(3.2) and R^(3.3);    -   R^(3.1) denotes spiro or het, while het may optionally be        substituted by one or more R^(3.11)        -   R^(3.1.1) denotes C₁₋₆-alkyl, C₂₋₆-alkenyl, OH,            C₁₋₄-alkylene-OH, C₁₋₄-alkylene-NR^(3.1.1.1)R^(3.1.1.2),            COR^(3.1.1.1), COOR^(3.1.1.1), CONR^(3.1.1.1)R^(3.1.1.2),            NR^(3.1.1.1)R^(3.1.1.2), het, hetaryl, NHCOR^(3.1.1.1),            -   R^(3.1.1.1) denotes a group selected from among H,                C₁₋₄-alkyl, aryl and C₇₋₁₁-aralkyl; optionally                substituted by a group selected from among halogen, OH                and CN;            -   R^(3.1.1.2) denotes H, C₁₋₄-alkyl;    -   R^(3.2) denotes a group selected from among C₃₋₆-cycloalkyl,        het, hetaryl and spiro which is optionally substituted by one or        more R^(3.2.1)        -   R^(3.2.1) denotes C₁₋₆-alkyl, C₃₋₆-cycloalkyl, OH,            —NR^(3.2.1.1)R^(3.2.1.2), NHCOR^(3.2.1.3) or het, optionally            substituted by one or more groups selected from among            C₁₋₄-alkyl, SO₂R^(3.2.1.1), CH₂—C₃₋₆-cycloalkyl and aryl;            -   R^(3.2.1.1) denotes H, C₁₋₄-alkyl or C₇₋₁₁- aralkyl;            -   R^(3.2.1.2) denotes H, C₁₋₄-alkyl or C₇₋₁₁- aralkyl;            -   R^(3.2.1.3) denotes aryl, C₇₋₁₁-aralkyl; or        -   —C₁₋₆-alkyl, which is optionally substituted by one or two            R^(3.2.2);        -   R^(3.2.2) denotes C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,            COOR^(3.2.2.1) CONR^(3.2.2.1)R^(3.2.2.2),            NR^(3.2.2.1)R^(3.2.2.2), NHCOR^(3.2.2.1), C₁₋₆-haloalkyl,            CN, OR^(3.2.2.1), SO₂R^(3.2.2.1), C₃₋₆-cycloalkyl, CO-het,            C₂₋₄-alkynyl-hetaryl, guanidine or a group selected from            among het, hetaryl and aryl, which is optionally substituted            by one or more groups selected from among halogen,            C₁₋₆-alkyl, CONR^(3.2.2.1)R^(3.2.2.2), OH, imidazolidinone;            -   R^(3.2.2.1) denotes H or C₁₋₆-alkyl, aryl, C₇₋₁₁-aralkyl            -   R^(3.2.2.2) denotes H or C₁₋₆-alkyl; or        -   aryl, which is optionally substituted by one or two            R^(3.2.3)        -   R^(3.2.3) denotes a group selected from among            NH—C₁₋₆-alkyl-N(C₁₋₆-alkyl)₂ or het, while het may            optionally be substituted by a C₁₋₆-alkyl group;    -   R^(3.3) denotes H or a group selected from among C₁₋₆-alkyl,        C₂₋₄-alkenyl, C₂₋₄-alkynyl and aryl, which may optionally be        substituted by one or more groups R^(3.3.1);        -   R^(3.3.1) denotes C₅₋₆-cycloalkyl, C₅₋₆-cycloalkenyl,            OR^(3.3.1.1), NR^(3.3.1.1)R^(3.3.1.2),            CONR^(3.3.1.1)R^(3.3.1.2), COOR^(3.3.1.1),            NR^(3.3.1.1)COR^(3.3.1.2), SOR^(3.3.1.1), SO₂R^(3.3.1.1),            C(NR^(3.3.1.1)R^(3.3.1.2))NR^(3.3.1.3),            NR^(3.3.1.1)CONR^(3.3.1.2)R^(3.3.1.3), OH, CN, halogen or            het, optionally substituted by one or more groups selected            from among C₁₋₄-alkyl, SO₂H, SO₂—C₁₋₄-alkyl,            SO₂C₇₋₁₁-aralkyl, CH₂—C₃₋₆-cycloalkyl and aryl;            -   R^(3.3.1.1), R^(3.3.1.2) and R^(3.3.1.3) denote a group                selected from among C₁₋₄-alkyl, C₇₋₁₁-aralkyl,                C₁₋₄-alkyl-hetaryl, COC₁₋₄-alkyl-hetaryl; or            -   two of the groups R^(3.3.1.1), R^(3.3.1.2) and                R^(3.3.1.3) together form a five-, six- or                seven-membered ring, consisting of carbon atoms and                optionally a heteroatom selected from among oxygen,                nitrogen and sulphur;

-   R^(a) denotes H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₆-cycloalkyl,    C₃₋₆-cycloalkenyl, C₁₋₆-haloalkyl, COR⁸, NR⁹R¹⁰, NO₂, OR⁸, SR¹¹,    SOR¹¹, SO₂R¹¹, NHCO—C₁₋₆-alkyl-NH₂, spiro or a group selected from    among C₇₋₁₁- aralkyl, CH₂—O-aryl and het which may optionally be    substituted by one or more halogens, C₁₋₆-alkyl, CO—C₁₋₄-haloalkyl,    C₁₋₄-alkyl-NH₂ or CH₂NHCOOR¹²;

-   R⁸ denotes C₁₋₆-alkyl, C₃₋₆-cycloalkyl, NH₂, hetaryl or aryl,    optionally substituted by one or more halogens or C₁₋₄-alkyl;

-   R⁹ denotes H, COOR¹² or C₁₋₄-alkyl, optionally substituted by one or    more COOH, N(C₁₋₄-alkyl)₂ or het, optionally substituted by one or    more C₁₋₄-alkyl; or R⁹ denotes het, optionally substituted by one or    more C₁₋₄-alkyl;

-   R¹⁰ denotes H, C₁₋₆-alkyl, CO—C₁₋₄-alkyl or C₂₋₆-alkynyl;

-   R¹¹ denotes C₁₋₆-alkyl, optionally substituted by one or more    N(C₁₋₄-alkyl)₂;

-   R¹² denotes C₁₋₆-alkyl;

-   R^(b) denotes R⁴, OR⁴, —CH₂OR⁴, COR⁴, COOR⁴, CONR⁴R⁵, NH₂, NR⁵COOR⁴,    NR⁵CONR⁴R⁵ or NR⁵SOR⁴;

-   R⁴ denotes H, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkylene-OH,    C₂₋₆-alkenyl, C₇₋₁₁-aralkyl, C₁₋₄-alkyl-hetaryl, C₂₋₆-alkynyl,    optionally substituted by Si(C₁₋₄-alkyl)₃, or R⁴ denotes a group    selected from among aryl, het, hetaryl and optionally substituted by    C₁₋₄-alkyl;

-   R⁵ denotes H or C₁₋₆-alkyl;    or R⁴ and R⁵ together form a five-, six- or seven-membered ring    consisting of carbon atoms and optionally a heteroatom selected from    among oxygen, nitrogen and sulphur;

-   R^(c) denotes NHR⁶ or a group selected from among

wherein

-   B denotes a bond, C₁₋₄-alkyl or C₂₋₄-alkynyl;-   R⁶ denotes H or a group selected from among C₁₋₄-alkyl,    C₃₋₆-cycloalkyl, het, aryl, hetaryl optionally substituted by one or    more groups R^(6.1);    -   R^(6.1) denotes halogen, CF₃, OH, CN, OMe, SO₂(C₁₋₄-alkyl);-   R⁷ denotes H, C₁₋₄-alkyl, C₃₋₆-cycloalkyl, NR^(7.1)R^(7.2),    OR^(7.2), SR^(7.2), hetaryl, het, optionally substituted by    C₁₋₄-alkyl or CONH₂;    -   R^(7.1) denotes H, C₁₋₄-alkyl, (CH₂)₂₋₄R^(7.1.1) or COObutyl;    -   R^(7.2) denotes H, C₁₋₆-alkyl, optionally substituted by one or        more OH;        -   R^(7.1.1) denotes NR^(7.1.1.1)R^(7.1.1.2), het or            1-imidazolyl, 2-(N-ethylpyrrolidine);            -   R^(7.1.1.1) denotes H or C₁₋₆-alkyl;            -   R^(7.1.1.2) denotes H or C₁₋₆-alkyl;                and the pharmacologically acceptable salts,                diastereomers, enantiomers, racemates, hydrates or                solvates thereof, with the proviso that R^(a) cannot be                H or Me if Y=nitrogen; Z=nitrogen; j=2; k=0; R^(b)=H and                R^(c)=NHCONH-Et.

Preferred compounds of formula 1 mentioned above are those wherein

-   R^(a) denotes a group selected from among aryl and C₇₋₁₁-aralkyl,    which may optionally be substituted by one or more groups selected    from among R¹, R² and R³; or hetaryl optionally substituted by one    or more C₁₋₄-alkyl;-   R¹ denotes C₁₋₄-alkyl, C₁₋₄-haloalkyl, C₁₋₄-alkylene-COOH,    C₁₋₄-alkoxy, halogen, OH, CN, COR^(1.1), O—C₁₋₄-haloalkyl, NO₂ or    SO₂R^(1.1);    -   R^(1.1) denotes OH, methyl, NH₂, NHMe, NMe₂,

-   R² denotes C₁₋₄-alkyl, C₁₋₄-alkoxy or halogen;-   R³ denotes a group selected from among

-   -   wherein    -   n denotes 0 or 1;    -   m denotes 0 or 1;    -   o denotes 2;    -   R^(3.1) denotes spiro or het, while het may optionally be        substituted by one or more R^(3.1.1);        -   R^(3.1.1) denotes C₁₋₄-alkyl, C₂₋₄-alkenyl, OH,            C₁₋₄-alkylene-OH, CH₂NEt₂, COMe, COOH, CONH₂, NH₂, het,            hetaryl,

-   -   R^(3.2) denotes a group selected from among C₃₋₆-cycloalkyl,        het, hetaryl and spiro which is optionally substituted by one or        two R^(3.2.1)        -   R^(3.2.1) denotes C₁₋₄-alkyl, cyclopentyl, OH,            —NR^(3.2.1.1)R^(3.2.1.2) or

-   -   -   -   or het, is optionally substituted by one or more groups                selected from among methyl, SO₂R^(3.2.1.1),

-   -   -   -   R^(3.2.1.1) denotes H, methyl or benzyl;            -   R^(3.2.1.2) denotes H, methyl or benzyl; or

        -   —C₁₋₆-alkyl, which is optionally substituted by one or two            R^(3.2.2);

        -   R^(3.2.2) denotes C₂₋₄-alkenyl, C₂₋₄-alkynyl, COOR^(3.2.2.1)            CONR^(3.2.2.1)R^(3.2.2.2), NR^(3.2.2.1)R^(3.2.2.2),            NHCOR^(3.2.2.1), C₁₋₄-haloalkyl, CN, OH, SO₂R^(3.2.2.1),            C₃₋₆-cycloalkyl or a group selected from among

-   -   -   -   or a group selected from among het, hetaryl and aryl,                which is optionally substituted by one or more groups                selected from among Cl, methyl,                CONR^(3.2.2.1)R^(3.2.2.2), OH;            -   R^(3.2.2.1) denotes H or methyl;            -   R^(3.2.2.2) denotes H or methyl; or

        -   aryl, which is optionally substituted by one or two            R^(3.2.3)

        -   R^(3.2.3) denotes a group selected from among

-   -   R^(3.3) denotes H or a group selected from among C₁₋₆-alkyl and        aryl, which may optionally be substituted by one or more groups        R^(3.3.1);        -   R^(3.3.1) denotes C₅₋₆-cycloalkyl, C₅₋₆-cycloalkenyl,            OR^(3.3.1.1), NR^(3.3.1.1)R^(3.3.1.2),            CONR^(3.3.1.1)R^(3.3.1.2), COOR^(3.3.1.1),            NR^(3.3.1.1)COR^(3.3.1.2), SOR^(3.3.1.1), SO₂R^(3.3.1.1),            C(NR^(3.3.1.1)R^(3.3.1.2))NR^(3.3.1.3),            NR^(3.3.1.1)CONR^(3.3.1.2)R^(3.3.1.3), OH, CN, halogen or            het, is optionally substituted by one or more groups            selected from among methyl, SO₂H, SO₂—C₁₋₄-alkyl,            SO₂C₇₋₁₁-aralkyl,

-   -   -   -   R^(3.3.1.1), R^(3.3.1.2) and R^(3.3.1.3) denote a group                selected from among C₁₋₄-alkyl, C₇₋₁₁-aralkyl,                C₁₋₄-alkyl-hetaryl, COC₁₋₄-alkyl-hetaryl;

-   R^(a) denotes H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₆-cycloalkyl, CF₃,    COR⁸, NR⁹R¹⁰, NO₂, S(O)_(n)R¹¹, or a group selected from among

-   -   or a group selected from among

-   -   which may optionally be substituted by one or more Cl;    -   or a group selected from among

-   -   which may optionally be substituted by one or more CH₃, COCF₃,        CH₂NH₂ or CH₂NHCOOR¹²;

-   R⁸ denotes C₁₋₄-alkyl, C₃₋₆-cycloalkyl, NH₂, furanyl or phenyl,    optionally substituted by one or more chlorine;

-   R⁹ denotes H, COOR¹² or piperidino, optionally substituted by one or    more CH₃, or a group selected from among C₁₋₄-alkyl, which may    optionally be substituted by one or more COOH, NMe₂ or    4-methylpiperazine;

-   R¹⁰ denotes H, C₁₋₄-alkyl, C₂₋₄-alkynyl or COCH₃;

-   R¹¹ denotes C₁₋₄-alkyl, optionally substituted by one or more NMe₂,

-   R¹² denotes C₁₋₄-alkyl;

-   R^(b) denotes R⁴, CH₂OR⁴, COR⁴, COOR⁴, CONR⁴R⁵, NH₂, NHCOOR⁴,    NHCONR⁴R⁵ or OH;

-   R⁴ denotes H, C₁₋₄-alkyl, C₁₋₄-alkylene-OH, C₂₋₄-alkynyl,    C₁₋₆-haloalkyl, aryl, het, hetaryl,

-   R⁵ denotes H or C₁₋₄-alkyl;-   R^(c) denotes NHR⁶ or a group selected from among

wherein

-   B denotes a bond, C₁₋₄-alkyl or C₂₋₄-alkynyl;-   R⁶ denotes H, C₁₋₄-alkyl, C₃₋₆-cycloalkyl, C₇₋₁₁- aralkyl, aryl,    optionally substituted by SO₂CH₃;-   R⁷ denotes H, NR^(7.1)R^(7.2), OR^(7.2), SR^(7.2), hetaryl, het,    optionally substituted by C₁₋₄-alkyl or CONH₂, or a group selected    from among

-   -   R^(7.1) denotes H, C₁₋₄-alkyl, (CH₂)₂R^(7.1.1) or COObutyl;    -   R^(7.2) denotes H, C₁₋₄-alkyl;        -   R^(7.1.1) denotes NR^(7.1.1.1)R^(7.1.1.2), het or            1-imidazolyl, 2-(N-ethylpyrrolidine);            -   R^(7.1.1.1) denotes H or C₁₋₆-alkyl;            -   R^(7.1.1.2) denotes H or C₁₋₆-alkyl;                and the pharmacologically acceptable salts,                diastereomers, enantiomers, racemates, hydrates or                solvates thereof, with the proviso that R^(a) cannot be                H or Me if Y=nitrogen; Z=nitrogen; j=2; k=0; R^(b)=H and                R^(c)=NHCONH-Et.

Preferred compounds of formula 1 mentioned above are those wherein

-   R^(a) denotes phenyl or benzyl, in each case optionally substituted    by one or more groups selected from among R¹, R² and R³; or

-   R¹ denotes methyl, ethyl, propyl, butyl, CF₃, CH₂COOH, methoxy, F,    Cl, Br, OH, CN, COR^(1.1), OCF₃, NO₂ or SO₂R^(1.1);    -   R^(1.1) denotes OH, methyl, NH₂, NHMe, NMe₂,

-   R² denotes methyl, methoxy, F, Cl or Br;-   R³ denotes a group selected from among

-   -   wherein    -   n denotes 0 or 1;    -   m denotes 0 or 1;    -   o denotes 2;    -   R^(3.1) denotes a group selected from among

-   -   -   or a group selected from among

-   -   -   which may optionally be substituted by one or more            R^(3.1.1);        -   R^(3.1.1) denotes methyl, ethyl, OH, CH₂OH, CH₂CH₂OH,            CH₂NEt₂, COMe, COOH, CONH₂, NH₂,

-   -   R^(3.2) denotes a group selected from among

-   -   -   which is optionally substituted by one or more groups            selected from among methyl, ethyl, cyclopentyl, OH, NH₂; or        -   cyclohexyl, which is optionally substituted by one or two            R^(3.2.1)        -   R^(3.2.1)—NR^(3.2.1.1)R^(3.2.1.2) or a group selected from            among

-   -   -   -   or a group selected from among

-   -   -   -   which is optionally substituted by one or more groups                selected from among methyl, SO₂R^(3.2.1.1),

-   -   -   -   R^(3.2.1.1) denotes H, methyl or benzyl;            -   R^(3.2.1.2) denotes H, methyl or benzyl; or

        -   —C₁₋₆-alkyl, straight-chain or branched, which is optionally            substituted by one or two R^(3.2.2);

        -   R^(3.2.2) denotes C═CH₂, C≡CH, COOR^(3.2.2.1),            CONR^(3.2.2.1)R^(3.2.2.2), NR^(3.2.2.1)R^(3.2.2.2),            NHCOR^(3.2.2.1), CF₃, CN, OH, SO₂R^(3.2.2.1) or a group            selected from among

-   -   -   -   or a group selected from among

-   -   -   -   which is optionally substituted by one or more groups                selected from among Cl, methyl,                CONR^(3.2.2.1)R^(3.2.2.2), OH;            -   R^(3.2.2.1) denotes H or methyl;            -   R^(3.2.2.2) denotes H or methyl; or

        -   phenyl, which is optionally substituted by one or two            R^(3.2.3)

        -   R^(3.2.3) denotes a group selected from among

-   -   R^(3.3) denotes H, C₁₋₆-alkyl, optionally substituted by one or        more R^(3.3.1.1),        -   R^(3.3.1) denotes C₅₋₆-cycloalkyl, C₅₋₆-cycloalkenyl,            OR^(3.3.1.1), NR^(3.3.1.1)R^(3.3.1.2),            CONR^(3.3.1.1)R^(3.3.1.2), COOR^(3.3.1.1),            NR^(3.3.1.1)COR^(3.3.1.2), SOR^(3.3.1.1), SO₂R^(3.3.1.1),            C(NR^(3.3.1.1)R^(3.3.1.2))NR^(3.3.1.3),            NR^(3.3.1.1)CONR^(3.3.1.2)R^(3.3.1.3), OH, CN, halogen or            het which is optionally substituted by one or more groups            selected from among methyl, SO₂H, SO₂Me, SO₂CH₂phenyl;

-   -   -   -   R^(3.3.1.1), R^(3.3.1.2) and R^(3.3.1.3) denote a group                selected from among C₁₋₄-alkyl, C₇₋₁₁-aralkyl,                C₁₋₄-alkyl-hetaryl, COC₁₋₄-alkyl-hetaryl;

-   R^(a) denotes H, methyl, ethyl, propyl, butyl, 3-methyl-butyl,    propenyl, cyclopropyl, cyclohexyl, CF₃, COR⁸, NR⁹R¹⁰, NO₂, OR⁸,    SR¹¹, SOR¹¹, SO₂R¹¹ or a group selected from among

-   -   or a group selected from among

-   -   which may optionally be substituted by one or more Cl,    -   or a group selected from among

-   -   which may optionally be substituted by one or more CH₃, COCF₃,        CH₂NH₂ or CH₂NHCOOR¹²;

-   R⁸ denotes methyl, propyl, cyclopropyl, NH₂, furanyl or phenyl,    optionally substituted by one or more chlorine;

-   R⁹ denotes H, COOR¹² or piperidino, optionally substituted by one or    more CH₃, or a group selected from among methyl, ethyl and propyl,    which may optionally be substituted by one or more COOH, NMe₂ or    4-methylpiperazine;

-   R¹⁰ denotes H, methyl, COCH₃, C≡CH or CH₂C≡CH;

-   R¹¹ denotes ethyl or propyl, optionally substituted by one or more    NMe₂,

-   R¹² denotes butyl

-   R^(b) denotes R⁴, CH₂OR⁴, COR⁴, COOR⁴, CONR⁴R⁵, NH₂, NHCOOR⁴,    NHCONR⁴R⁵ or OH;

-   R⁴ denotes H, methyl, ethyl, 2-hydroxyethyl, propyl, C≡CH, CF₃,    phenyl,

-   R⁵ denotes H, methyl or ethyl;-   R^(c) denotes NHR⁶ or a group selected from among

wherein

-   B denotes a bond, methylene, ethylene, propylene or butynylene;-   R⁶ denotes H, C₁₋₄-alkyl, aryl, optionally substituted by SO₂CH₃;-   R⁷ denotes H, NR^(7.1)R^(7.2), OR^(7.2), SR^(7.2) or a group    selected from among

-   -   R^(7.1) denotes H, methyl, ethyl, (CH₂)₂R^(7.1.1) or COObutyl;    -   R^(7.2) denotes H, methyl or ethyl;        -   R^(7.1.1) denotes NR^(7.1.1.1)R^(7.1.1.2), het or            1-imidazolyl, 2-(N-ethylpyrrolidine);            -   R^(7.1.1.1) denotes H or C₁₋₆-alkyl;            -   R^(7.1.1.2) denotes H or C₁₋₆-alkyl;                and the pharmacologically acceptable salts,                diastereomers, enantiomers, racemates, hydrates or                solvates thereof, with the proviso that R^(a) cannot be                H or Me if Y=nitrogen; Z=nitrogen; j=2; k=0; R^(b)=H and                R^(c)=NHCONH-Et.

Preferred compounds of formula 1 mentioned above are those wherein

-   R^(a) denotes a group selected from among aryl, C₇₋₁₁-aralkyl and    hetaryl, which may optionally be substituted by one or more groups    selected from among R¹, R² and R³;-   R¹ and R² independently of one another denote C₁₋₆-alkyl,    C₂₋₆-alkenyl C₂₋₆-alkynyl, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkenyl,    C₁₋₆-haloalkyl, C₁₋₆-alkylene-COOH, C₁₋₆-alkoxy, halogen, OH, CN,    COR^(1.1), O—C₁₋₄-haloalkyl, NO₂ or SR^(1.1), SOR^(1.1), SO₂R^(1.1),    het or hetaryl,    -   R^(1.1.1) denotes OH, C₁₋₆-alkyl, C₂₋₆-alkenyl C₂₋₆-alkynyl,        NR^(1.1.1)R^(1.1.2)        -   R^(1.1.1) denotes H, C₁₋₆-alkyl, optionally substituted by a            group selected from among NH₂, NHMe, NMe₂;        -   R^(1.1.2) denotes H, C₁₋₆-alkyl;        -   or R^(1.1.1) and R^(1.1.2) together form a five- or            six-membered heterocyclic ring, which may optionally be            substituted by a group selected from among methyl, ethyl,            propyl;-   R³ denotes a group selected from among

-   -   wherein    -   X denotes a bond or C₁₋₄-alkylene;    -   R^(3a) denotes a group, which may be identical or different,        selected from among R^(3.1), R^(3.2) and R^(3.3);    -   R^(3.1) denotes spiro or het, while het may optionally be        substituted by one or more R^(3.1.1);        -   R^(3.1.1) denotes C₁₋₆-alkyl, C₂₋₆-alkenyl, OH,            C₁₋₄-alkylene-OH, C₁₋₄-alkylene-NR^(3.1.1.1)R^(3.1.1.2),            COR^(3.1.1.1), COOR^(3.1.1.1), CONR^(3.1.1.1)R^(3.1.1.2),            NR^(3.1.1.1)R^(3.1.1.2), het, hetaryl, NHCOR^(3.1.1.1)            -   R^(3.1.1.1) denotes a group selected from among H,                C₁₋₄-alkyl, aryl and C₇₋₁₁-aralkyl; optionally                substituted by a group selected from among halogen, OH                and CN;            -   R^(3.1.1.2) denotes H, C₁₋₄-alkyl;    -   R^(3.2) denotes a group selected from among C₃₋₆-cycloalkyl,        het, hetaryl and spiro which is optionally substituted by one or        more R^(3.2.1)        -   R^(3.2.1) denotes C₁₋₆-alkyl, C₃₋₆-cycloalkyl, OH,            NR^(3.2.1.1)R^(3.2.1.2), NHCOR^(3.2.1.3) or het, optionally            substituted by one or more groups selected from among            C₁₋₄-alkyl, SO₂R^(3.2.1.1), CH₂—C₃₋₆-cycloalkyl and aryl;            -   R^(3.2.1.1) denotes H, C₁₋₄-alkyl or C₇₋₁₁- aralkyl;            -   R^(3.2.1.2) denotes H, C₁₋₄-alkyl or C₇₋₁₁- aralkyl;            -   R^(3.2.1.3) denotes aryl, C₇₋₁₁-aralkyl; or        -   C₁₋₆-alkyl, which is optionally substituted by one or two            R^(3.2.2);        -   R^(3.2.2) denotes C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,            COOR^(3.2.2.1), CONR^(3.2.2.1)R^(3.2.2.2),            NR^(3.2.2.1)R^(3.2.2.2), NHCOR^(3.2.2.1), C₁₋₆-haloalkyl,            CN, OR^(3.2.2.1), SO₂R^(3.2.2.1), C₃₋₆-cycloalkyl, CO-het,            C₂₋₄-alkynyl-hetaryl, guanidine or a group selected from            among het, hetaryl and aryl, which is optionally substituted            by one or more groups selected from among halogen,            C₁₋₆-alkyl, CONR^(3.2.2.1)R^(3.2.2.2), OH, imidazolidinone;            -   R^(3.2.2.1) denotes H or C₁₋₆-alkyl, aryl, C₇₋₁₁-aralkyl            -   R^(3.2.2.2) denotes H or C₁₋₆-alkyl; or        -   aryl, which is optionally substituted by one or two            R^(3.2.3)        -   R^(3.2.3) denotes a group selected from among            NH—C₁₋₆-alkyl-N(C₁₋₆-alkyl)₂ or het, while het may            optionally be substituted by a C₁₋₆-alkyl group;    -   R^(3.3) denotes H or a group selected from among C₁₋₆-alkyl,        C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-haloalkyl and aryl, which may        optionally be substituted by one or more groups R^(3.3.1);        -   R^(3.3.1) denotes C₃₋₆-cycloalkyl, C₃₋₆-cycloalkenyl,            OR^(3.3.1.1), NR^(3.3.1.1)R^(3.3.1.2),            CONR^(3.3.1.1)R^(3.3.1.2), COOR^(3.3.1.1),            NR^(3.3.1.1)COR^(3.3.1.2), SOR^(3.3.1.1), SO₂R^(3.3.1.1),            C(NR^(3.3.1.1)R^(3.3.1.2))NR^(3.3.1.3),            NR^(3.3.1.1)CONR^(3.3.1.2)R^(3.3.1.3), OH, CN, halogen or            het, optionally substituted by one or more groups selected            from among C₁₋₄-alkyl, SO₂R^(3.2.1.1), SO₂C₁₋₄-alkyl,            SO₂C₇₋₁₁- aralkyl, CH₂—C₃₋₆-cycloalkyl and aryl;            -   R^(3.3.1.1), R^(3.3.1.2) and R^(3.3.1.3) denote a group                selected from among C₁₋₆-alkyl, C₂₋₆-alkenyl,                C₂₋₆-alkynyl, C₇₋₁₁-aralkyl, C₂₋₄-alkenyl-aryl,                C₂₋₄-alkynyl-aryl, C₁₋₄-alkyl-hetaryl,                C₂₋₄-alkenyl-hetaryl, C₂₋₄-alkynyl-hetaryl,                COC₁₋₄-alkyl-hetaryl, COC₂₋₄-alkenyl-hetaryl,                COC₂₋₄-alkynyl-hetaryl; or            -   two of the groups R^(3.3.1.1), R^(3.3.1.2) and                R^(3.3.1.3) together form a ring, consisting of carbon                atoms and optionally a heteroatom selected from among                oxygen, nitrogen and sulphur;

-   R^(b) denotes R⁴, OR⁴, —CH₂OR⁴, COR⁴, COOR⁴, CONR⁴R⁵, NR⁴R⁵,    NR⁵COR⁴, NR⁵COOR⁴, NR⁵CONR⁴R⁵, NR⁵SOR⁴ or NR⁵SO₂R⁴;

-   R⁴, R⁵ denote H, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkylene-OH,    C₂₋₆-alkenyl, C₇₋₁₁-aralkyl, C₂₋₄-alkenyl-aryl, C₂₋₄-alkynyl-aryl,    C₁₋₄-alkyl-hetaryl, C₂₋₄-alkenyl-hetaryl, C₂₋₄-alkynyl-hetaryl,    C₂₋₆-alkynyl, optionally substituted by Si(C₁₋₄-alkyl)₃, or R⁴    denotes a group selected from among aryl, het, hetaryl and    optionally substituted by C₁₋₄-alkyl;    or R⁴ and R⁵ together form a five-, six- or seven-membered ring    consisting of carbon atoms and optionally a heteroatom selected from    among oxygen, nitrogen and sulphur;

-   R^(c) denotes NHR⁶ or a group selected from among

wherein

-   B denotes a bond, C₁₋₆-alkyl, C₂₋₆-alkenyl or C₂₋₆-alkynyl;-   R⁶ denotes H or a group selected from among C₁₋₄-alkyl,    C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkenyl, het,    aryl, hetaryl optionally substituted by one or more groups R^(6.1);    -   R^(6.1) denotes halogen, CF₃, OH, CN, OMe, SO₂(C₁₋₄-alkyl);-   R⁷ denotes H, C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl,    C₃₋₆-cycloalkyl, NR^(7.1)R^(7.2), OR^(7.2), SR^(7.2), hetaryl, het,    optionally substituted by C₁₋₄-alkyl or CONH₂;    -   R^(7.1) denotes H, C₁₋₆-alkyl, (CH₂)₂₋₄R^(7.1.1) or COObutyl;    -   R^(7.2) denotes H, C₁₋₆-alkyl, optionally substituted by one or        more OH;        -   R^(7.1.1) denotes NR^(7.1.1.1)R^(7.1.1.2), het or            1-imidazolyl, 2-(N-ethylpyrrolidine);            -   R^(7.1.1.1) denotes H or C₁₋₆-alkyl;            -   R^(7.1.1.2) denotes H or C₁₋₆-alkyl;                and the pharmacologically acceptable salts,                diastereomers, enantiomers, racemates, hydrates or                solvates thereof.

Preferred compounds of formula 1 mentioned above are those wherein

-   R^(a) denotes a group selected from among aryl, C₇₋₁₁-aralkyl and    hetaryl, which may optionally be substituted by one or more groups    selected from among R¹, R² and R³;-   R¹ and R² independently of one another denote C₁₋₆-alkyl,    C₂₋₆-alkenyl C₂₋₆-alkynyl, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkenyl,    C₁₋₆-haloalkyl, C₁₋₆-alkylene-COOH, C₁₋₆-alkoxy, halogen, OH, CN,    COR^(1.1), O—C₁₋₄-haloalkyl, NO₂ or SR^(1.1), SOR^(1.1), SO₂R^(1.1),    het or hetaryl,    -   R^(1.1) denotes OH, C₁₋₆-alkyl, C₂₋₆-alkenyl C₂₋₆-alkynyl,        NR^(1.1.1)R^(1.1.2)        -   R^(1.1.1) denotes H, C₁₋₆-alkyl, optionally substituted by a            group selected from among NH₂, NHMe, NMe₂;        -   R^(1.1.2) denotes H, C₁₋₆-alkyl;        -   or R^(1.1.1) and R^(1.1.2) together form a five- or            six-membered heterocyclic ring, which may optionally be            substituted by a group selected from among methyl, ethyl,            propyl;-   R³ denotes a group selected from among

-   -   wherein    -   X denotes a bond or C₁₋₄-alkylene;    -   R^(3a) denotes a group, which may be identical or different,        selected from among R^(3.1), R^(3.2) and R^(3.3)    -   R^(3.1) denotes spiro or het, while het may optionally be        substituted by one or more R^(3.1.1);        -   R^(3.1.1) denotes C₁₋₆-alkyl, C₂₋₆-alkenyl, OH,            C₁₋₄-alkylene-OH, C₁₋₄-alkylene-NR^(3.1.1.1)R^(3.1.1.2),            COR^(3.1.1.1), COOR^(3.1.1.1), CONR^(3.1.1.1)R^(3.1.1.2),            NR^(3.1.1.1)R^(3.1.1.2), het, hetaryl, NHCOR^(3.1.1.1)            -   R^(3.1.1.1) denotes a group selected from among H,                C₁₋₄-alkyl, aryl and C₇₋₁₁-aralkyl; optionally                substituted by a group selected from among halogen, OH                and CN;            -   R^(3.1.1.2) denotes H, C₁₋₄-alkyl;    -   R^(3.2) denotes a group selected from among C₃₋₆-cycloalkyl,        het, hetaryl and spiro which is optionally substituted by one or        more R^(3.2.1)        -   R^(3.2.1) denotes C₁₋₆-alkyl, C₃₋₆-cycloalkyl, OH,            —NR^(3.2.1.1)R^(3.2.1.2), NHCOR^(3.2.1.3) or het, optionally            substituted by one or more groups selected from among            C₁₋₄-alkyl, SO₂R^(3.2.1.1), CH₂—C₃₋₆-cycloalkyl and aryl;            -   R^(3.2.1.1) denotes H, C₁₋₄-alkyl or C₇₋₁₁- aralkyl;            -   R^(3.2.1.2) denotes H, C₁₋₄-alkyl or C₇₋₁₁- aralkyl;            -   R^(3.2.1.3) denotes aryl, C₇₋₁₁-aralkyl; or        -   —C₁₋₆-alkyl, which is optionally substituted by one or two            R^(3.2.2);        -   R^(3.2.2) denotes C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,            COOR^(3.2.2.1), CONR^(3.2.2.1)R^(3.2.2.2),            NR^(3.2.2.1)R^(3.2.2.2), NHCOR^(3.2.2.1), C₁₋₆-haloalkyl,            CN, OR^(3.2.2.1), SO₂R^(3.2.2.1), C₃₋₆-cycloalkyl, CO-het,            C₂₋₄-alkynyl-hetaryl, guanidine or a group selected from            among het, hetaryl and aryl, which is optionally substituted            by one or more groups selected from among halogen,            C₁₋₆-alkyl, CONR^(3.2.2.1)R^(3.2.2.2), OH, imidazolidinone;            -   R^(3.2.2.1) denotes H or C₁₋₆-alkyl, aryl, C₇₋₁₁-aralkyl            -   R^(3.2.2.2) denotes H or C₁₋₆-alkyl; or        -   aryl, which is optionally substituted by one or two            R^(3.2.3)        -   R^(3.2.3) denotes a group selected from among            NH—C₁₋₆-alkyl-N(C₁₋₆-alkyl)₂ or het, while het may            optionally be substituted by a C₁₋₆-alkyl group;    -   R^(3.3) denotes H or a group selected from among C₁₋₆-alkyl,        C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₁₋₄-haloalkyl and aryl, which may        optionally be substituted by one or more groups R^(3.3.1);        -   R^(3.3.1) denotes C₅₋₆-cycloalkyl, C₅₋₆-cycloalkenyl,            OR^(3.3.1.1), NR^(3.3.1.1)R^(3.3.1.2),            CONR^(3.3.1.1)R^(3.3.1.2), COOR^(3.3.1.1),            NR^(3.3.1.1)COR^(3.3.1.2), SOR^(3.3.1.1), SO₂R^(3.3.1.1),            C(NR^(3.3.1.1)R^(3.3.1.2))NR^(3.3.1.3),            NR^(3.3.1.1)CONR^(3.3.1.2)R^(3.3.1.3), OH, CN, halogen or            het, optionally substituted by one or more groups selected            from among C₁₋₄-alkyl, SO₂R^(3.2.1.1), SO₂C₁₋₄-alkyl,            SO₂C₇₋₁₁- aralkyl, CH₂—C₃₋₆-cycloalkyl and aryl;            -   R^(3.3.1.1), R^(3.3.1.2) and R^(3.3.1.3) denote a group                selected from among C₁₋₄-alkyl, C₂₋₄-alkenyl,                C₂₋₄-alkynyl, C₇₋₁₁-aralkyl, C₂₋₄-alkenyl-aryl,                C₂₋₄-alkynyl-aryl, C₁₋₄-alkyl-hetaryl,                C₂₋₄-alkenyl-hetaryl, C₂₋₄-alkynyl-hetaryl,                COC₁₋₄-alkyl-hetaryl, COC₂₋₄-alkenyl-hetaryl,                COC₂₋₄-alkynyl-hetaryl; or            -   two of the groups R^(3.3.1.1), R^(3.3.1.2) and                R^(3.3.1.3) together form a five-, six- or                seven-membered ring, consisting of carbon atoms and                optionally a heteroatom selected from among oxygen,                nitrogen and sulphur;

-   R^(b) denotes R⁴, OR⁴, —CH₂OR⁴, COR⁴, COOR⁴, CONR⁴R⁵, NR⁴R⁵,    NR⁵COR⁴, NR⁵COOR⁴, NR⁵CONR⁴R⁵, NR⁵SOR⁴ or NR⁵SO₂R⁴;

-   R⁴ denotes H, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkylene-OH,    C₂₋₆-alkenyl, C₇₋₁₁-aralkyl, C₂₋₄-alkenyl-aryl, C₂₋₄-alkynyl-aryl,    C₁₋₄-alkyl-hetaryl, C₂₋₄-alkenyl-hetaryl, C₂₋₄-alkynyl-hetaryl,    C₂₋₆-alkynyl, optionally substituted by Si(C₁₋₄-alkyl)₃, or R⁴    denotes a group selected from among aryl, het, hetaryl and    optionally substituted by C₁₋₄-alkyl;

-   R⁵ denotes H or C₁₋₆-alkyl;    or R⁴ and R⁵ together form a five-, six- or seven-membered ring    consisting of carbon atoms and optionally a heteroatom selected from    among oxygen, nitrogen and sulphur;

-   R^(c) denotes NHR⁶ or a group selected from among

wherein

-   B denotes a bond, C₁₋₄-alkyl or C₂₋₄-alkynyl;-   R⁶ denotes H or a group selected from among C₁₋₄-alkyl,    C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkenyl, het,    aryl, hetaryl optionally substituted by one or more groups R^(6.1);    -   R^(6.1) denotes halogen, CF₃, OH, CN, OMe, SO₂(C₁₋₄-alkyl);-   R⁷ denotes H, C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl,    C₃₋₆-cycloalkyl, NR^(7.1)R^(7.2), OR^(7.2), SR^(7.2), hetaryl, het,    optionally substituted by C₁₋₄-alkyl or CONH₂;    -   R^(7.1) denotes H, C₁₋₄-alkyl, (CH₂)₂₋₄R^(7.1.1) or COObutyl;    -   R^(7.2) denotes H, C₁₋₆-alkyl, optionally substituted by one or        more OH;        -   R^(7.1.1) denotes NR^(7.1.1.1)R^(7.1.1.2), het or            1-imidazolyl, 2-(N-ethylpyrrolidine);            -   R^(7.1.1.1) denotes H or C₁₋₆-alkyl;            -   R^(7.1.1.2) denotes H or C₁₋₆-alkyl;                and the pharmacologically acceptable salts,                diastereomers, enantiomers, racemates, hydrates or                solvates thereof.

Preferred compounds of formula 1 mentioned above are those wherein

-   R^(a) denotes a group selected from among aryl, C₇₋₁₁-aralkyl and    hetaryl, which may optionally be substituted by one or more groups    selected from among R¹, R² and R³;-   R¹ and R² independently of one another denote C₁₋₆-alkyl,    C₂₋₆-alkenyl C₂₋₆-alkynyl, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkenyl,    C₁₋₆-haloalkyl, C₁₋₆-alkylene-COOH, C₁₋₆-alkoxy, halogen, OH, CN,    COR^(1.1), O—C₁₋₄-haloalkyl, NO₂ or SR^(1.1), SOR^(1.1), SO₂R^(1.1),    het or hetaryl,    -   R^(1.1) denotes OH, C₁₋₆-alkyl, C₂₋₆-alkenyl C₂₋₆-alkynyl,        NR^(1.1.1)R^(1.1.2)        -   R^(1.1.1) denotes H, C₁₋₆-alkyl, optionally substituted by a            group selected from among NH₂, NHMe, NMe₂;        -   R^(1.1.2) denotes H, C₁₋₆-alkyl;        -   or R^(1.1.1) and R^(1.1.2) together form a five- or            six-membered heterocyclic ring, which may optionally be            substituted by a group selected from among methyl, ethyl,            propyl;-   R³ denotes a group selected from among

-   -   wherein    -   X denotes a bond or C₁₋₄-alkylene;    -   R^(3a) denotes a group, which may be identical or different,        selected from among R^(3.1), R^(3.2) and R^(3.3)    -   R^(3.1) denotes spiro or het, while het may optionally be        substituted by one or more R^(3.1.1);        -   R^(3.1.1) denotes C₁₋₆-alkyl, C₂₋₆-alkenyl, OH,            C₁₋₄-alkylene-OH, C₁₋₄-alkylene-NR^(3.1.1.1)R^(3.1.1.2),            COR^(3.1.1.1), COOR^(3.1.1.1), CONR^(3.1.1.1)R^(3.1.1.2),            NR^(3.1.1.1)R^(3.1.1.2), het, hetaryl, NHCOR^(3.1.1.1)            -   R^(3.1.1.1) denotes a group selected from among H,                C₁₋₄-alkyl, aryl and C₇₋₁₁-aralkyl; optionally                substituted by a group selected from among halogen, OH                and CN;            -   R^(3.1.1.2) denotes H, C₁₋₄-alkyl;    -   R^(3.2) denotes a group selected from among C₃₋₆-cycloalkyl,        het, hetaryl and spiro which is optionally substituted by one or        more R^(3.2.1)        -   R^(3.2.1) denotes C₁₋₆-alkyl, C₃₋₆-cycloalkyl, OH,            —NR^(3.2.1.1)R^(3.2.1.2), NHCOR^(3.2.1.3) or het, optionally            substituted by one or more groups selected from among            C₁₋₄-alkyl, SO₂R^(3.2.1.1), CH₂—C₃₋₆-cycloalkyl and aryl;            -   R^(3.2.1.1) denotes H, C₁₋₄-alkyl or C₇₋₁₁- aralkyl;            -   R^(3.2.1.2) denotes H, C₁₋₄-alkyl or C₇₋₁₁- aralkyl;            -   R^(3.2.1.3) denotes aryl, C₇₋₁₁-aralkyl; or        -   C₁₋₆-alkyl, which is optionally substituted by one or two            R^(3.2.2);        -   R^(3.2.2) denotes C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,            COOR^(3.2.2.1), CONR^(3.2.2.1)R^(3.2.2.2),            NR^(3.2.2.1)R^(3.2.2.2), NHCOR^(3.2.2.1), C₁₋₆-haloalkyl,            CN, OR^(3.2.2.1), SO₂R^(3.2.2.1), C₃₋₆-cycloalkyl, CO-het,            C₂₋₄-alkynyl-hetaryl, guanidine or a group selected from            among het, hetaryl and aryl, which is optionally substituted            by one or more groups selected from among halogen,            C₁₋₆-alkyl, CONR^(3.2.2.1)R^(3.2.2.2), OH, imidazolidinone;            -   R^(3.2.2.1) denotes H or C₁₋₆-alkyl, aryl, C₇₋₁₁-aralkyl            -   R^(3.2.2.2) denotes H or C₁₋₆-alkyl; or        -   aryl, which is optionally substituted by one or two            R^(3.2.3)        -   R^(3.2.3) denotes a group selected from among            NH—C₁₋₆-alkyl-N(C₁₋₆-alkyl)₂ or het, while het may            optionally be substituted by a C₁₋₆-alkyl group;    -   R^(3.3) denotes H or a group selected from among C₁₋₆-alkyl,        C₂₋₄-alkenyl, C₂₋₄-alkynyl and aryl, which may optionally be        substituted by one or more groups R^(3.3.1);        -   R^(3.3.1) denotes C₅₋₆-cycloalkyl, C₅₋₆-cycloalkenyl,            OR^(3.3.1.1), NR^(3.3.1.1)R^(3.3.1.2),            CONR^(3.3.1.1)R^(3.3.1.2), COOR^(3.3.1.1),            NR^(3.3.1.1)COR^(3.3.1.2), SOR^(3.3.1.1), SO₂R^(3.3.1.1),            C(NR^(3.3.1.1)R^(3.3.1.2))NR^(3.3.1.3),            NR^(3.3.1.1)CONR^(3.3.1.2)R^(3.3.1.3), OH, CN, halogen or            het, optionally substituted by one or more groups selected            from among C₁₋₄-alkyl, SO₂R^(3.2.1.1), SO₂C₁₋₄-alkyl,            SO₂C₇₋₁₁- aralkyl, CH₂—C₃₋₆-cycloalkyl and aryl;            -   R^(3.3.1.1), R^(3.3.1.2) and R^(3.3.1.3) denote a group                selected from among C₁₋₄-alkyl, C₇₋₁₁-aralkyl,                C₁₋₄-alkyl-hetaryl, COC₁₋₄-alkyl-hetaryl; or            -   two of the groups R^(3.3.1.1), R^(3.3.1.2) and                R^(3.3.1.3) together form a five-, six- or                seven-membered ring, consisting of carbon atoms and                optionally a heteroatom selected from among oxygen,                nitrogen and sulphur;

-   R^(b) denotes R⁴, OR⁴, —CH₂OR⁴, COR⁴, COOR⁴, CONR⁴R⁵, NH₂, NR⁵COOR⁴,    NR⁵CONR⁴R⁵ or NR⁵SOR⁴;

-   R⁴ denotes H, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkylene-OH,    C₂₋₆-alkenyl, C₇₋₁₁-aralkyl, C₁₋₄-alkyl-hetaryl, C₂₋₆-alkynyl,    optionally substituted by Si(C₁₋₄-alkyl)₃, or R⁴ denotes a group    selected from among aryl, het, hetaryl and optionally substituted by    C₁₋₄-alkyl;

-   R⁵ denotes H or C₁₋₆-alkyl;    or R⁴ and R⁵ together form a five-, six- or seven-membered ring    consisting of carbon atoms and optionally a heteroatom selected from    among oxygen, nitrogen and sulphur;

-   R^(c) denotes NHR⁶ or a group selected from among

wherein

-   B denotes a bond, C₁₋₄-alkyl or C₂₋₄-alkynyl;-   R⁶ denotes H or a group selected from among C₁₋₄-alkyl,    C₃₋₆-cycloalkyl, het, aryl, hetaryl optionally substituted by one or    more groups R^(6.1);    -   R^(6.1) denotes halogen, CF₃, OH, CN, OMe, SO₂(C₁₋₄-alkyl);-   R⁷ denotes H, C₁₋₄-alkyl, C₃₋₆-cycloalkyl, NR^(7.1)R^(7.2),    OR^(7.2), SR^(7.2), hetaryl, het, optionally substituted by    C₁₋₄-alkyl or CONH₂;    -   R^(7.1) denotes H, C₁₋₄-alkyl, (CH₂)₂₋₄R^(7.1.1) or COObutyl;    -   R^(7.2) denotes H, C₁₋₆-alkyl, optionally substituted by one or        more OH;        -   R^(7.1.1) denotes NR^(7.1.1.1)R^(7.1.1.2), het or            1-imidazolyl, 2-(N-ethylpyrrolidine);            -   R^(7.1.1.1) denotes H or C₁₋₆-alkyl;            -   R^(7.1.1.2) denotes H or C₁₋₆-alkyl;                and the pharmacologically acceptable salts,                diastereomers, enantiomers, racemates, hydrates or                solvates thereof.

Preferred compounds of formula 1 mentioned above are those wherein

-   R^(a) denotes a group selected from among aryl and C₇₋₁₁-aralkyl,    which may optionally be substituted by one or more groups selected    from among R¹, R² and R³; or hetaryl optionally substituted by one    or more C₁₋₄-alkyl;-   R¹ denotes C₁₋₄-alkyl, C₁₋₄-haloalkyl, C₁₋₄-alkylene-COOH,    C₁₋₄-alkoxy, halogen, OH, CN, COR^(1.1), O—C₁₋₄-haloalkyl, NO₂ or    SO₂R^(1.1);    -   R^(1.1) denotes OH, methyl, NH₂, NHMe, NMe₂,

-   R² denotes C₁₋₄-alkyl, C₁₋₄-alkoxy or halogen;-   R³ denotes a group selected from among

-   -   wherein    -   n denotes 0 or 1;    -   m denotes 0 or 1;    -   o denotes 2;    -   R^(3.1) denotes spiro or het, while het may optionally be        substituted by one or more R^(3.1.1);        -   R^(3.1.1) denotes C₁₋₄-alkyl, C₂₋₄-alkenyl, OH,            C₁₋₄-alkylene-OH, CH₂NEt₂, COMe, COOH, CONH₂, NH₂, het,            hetaryl,

-   -   R^(3.2) denotes a group selected from among C₃₋₆-cycloalkyl,        het, hetaryl and spiro which is optionally substituted by one or        two R^(3.2.1)        -   R^(3.2.1) denotes C₁₋₄-alkyl, cyclopentyl, OH,            —NR^(3.2.1.1)R^(3.2.1.2) or

-   -   -   -   or het, is optionally substituted by one or more groups                selected from among methyl, SO₂R^(3.2.1.1),

-   -   -   -   R^(3.2.1.1) denotes H, methyl or benzyl;            -   R^(3.2.1.2) denotes H, methyl or benzyl; or

        -   C₁₋₆-alkyl, which is optionally substituted by one or two            R^(3.2.2);

        -   R^(3.2.2) denotes C₂₋₄-alkenyl, C₂₋₄-alkynyl, COOR^(3.2.2.1)            CONR^(3.2.2.1)R^(3.2.2.2), NR^(3.2.2.1)R^(3.2.2.2),            NHCOR^(3.2.2.1), C₁₋₄-haloalkyl, CN, OH, SO₂R^(3.2.2.1),            C₃₋₆-cycloalkyl or a group selected from among

-   -   -   -   or a group selected from among het, hetaryl and aryl,                which is optionally substituted by one or more groups                selected from among Cl, methyl,                CONR^(3.2.2.1)R^(3.2.2.2), OH;            -   R^(3.2.2.1) denotes H or methyl;            -   R^(3.2.2.2) denotes H or methyl; or

        -   aryl, which is optionally substituted by one or two            R^(3.2.3)

        -   R^(3.2.3) denotes a group selected from among

-   -   R^(3.3) denotes H or a group selected from among C₁₋₆-alkyl and        aryl, which may optionally be substituted by one or more groups        R^(3.3.1);        -   R^(3.3.1) denotes C₅₋₆-cycloalkyl, C₅₋₆-cycloalkenyl,            OR^(3.3.1.1), NR^(3.3.1.1)R^(3.3.1.2),            CONR^(3.3.1.1)R^(3.3.1.2), COOR^(3.3.1.1),            NR^(3.3.1.1)COR^(3.3.1.2), SOR^(3.3.1.1), SO₂R^(3.3.1.1),            C(NR^(3.3.1.1)R^(3.3.1.2))NR^(3.3.1.3),            NR^(3.3.1.1)CONR^(3.3.1.2)R^(3.3.1.3), OH, CN, halogen or            het, optionally substituted by one or more groups selected            from among C₁₋₄-alkyl, SO₂R^(3.2.1.1), SO₂C₁₋₄-alkyl,            SO₂C₇₋₁₁- aralkyl,

-   -   -   R^(3.3.1.1), R^(3.3.1.2) and R^(3.3.1.3) denote a group            selected from among C₁₋₄-alkyl, C₇₋₁₁-aralkyl,            C₁₋₄-alkyl-hetaryl, COC₁₋₄-alkyl-hetaryl;

-   R^(b) denotes R⁴, CH₂OR⁴, COR⁴, COOR⁴, CONR⁴R⁵, NH₂, NHCOOR⁴,    NHCONR⁴R⁵ or OH;

-   R⁴ denotes H, C₁₋₄-alkyl, C₁₋₄-alkylene-OH, C₂₋₄-alkynyl,    C₁₋₆-haloalkyl, aryl, het, hetaryl,

-   R⁵ denotes H or C₁₋₄-alkyl;-   R^(c) denotes NHR⁶ or a group selected from among

wherein

-   B denotes a bond, C₁₋₄-alkyl or C₂₋₄-alkynyl;-   R⁶ denotes H, C₁₋₄-alkyl, C₃₋₆-cycloalkyl, C₇₋₁₁- aralkyl, aryl,    optionally substituted by SO₂CH₃;-   R⁷ denotes H, NR^(7.1)R^(7.2), OR^(7.2), SR^(7.2), hetaryl, het,    optionally substituted by C₁₋₄-alkyl or CONH₂, or a group selected    from among

-   -   R^(7.1) denotes H, C₁₋₄-alkyl, (CH₂)₂R^(7.1.1) or COObutyl;    -   R^(7.2) denotes H, C₁₋₄-alkyl;        -   R^(7.1.1) denotes NR^(7.1.1.1)R^(7.1.1.2), het or            1-imidazolyl, 2-(N-ethylpyrrolidine);            -   R^(7.1.1.1) denotes H or C₁₋₆-alkyl;            -   R^(7.1.1.2) denotes H or C₁₋₆-alkyl;                and the pharmacologically acceptable salts,                diastereomers, enantiomers, racemates, hydrates or                solvates thereof.

Particularly preferred are the above-mentioned compounds of formula 1wherein

-   R^(a) denotes phenyl or benzyl, in each case optionally substituted    by one or more groups selected from among R¹, R² and R³; or

-   R¹ denotes methyl, ethyl, propyl, butyl, CF₃, CH₂COOH, methoxy, F,    Cl, Br, OH, CN, COR^(1.1), OCF₃, NO₂ or SO₂R^(1.1);    -   R^(1.1) denotes OH, methyl, NH₂, NHMe, NMe₂,

-   R² denotes methyl, methoxy, F, Cl or Br;-   R³ denotes a group selected from among

-   -   wherein    -   n denotes 0 or 1;    -   m denotes 0 or 1;    -   o denotes 2;    -   R^(3.1) denotes a group selected from among

-   -   -   or a group selected from among

-   -   -   which may optionally be substituted by one or more            R^(3.1.1);        -   R^(3.1.1) denotes methyl, ethyl, OH, CH₂OH, CH₂CH₂OH,            CH₂NEt₂, COMe, COOH, CONH₂, NH₂,

-   -   R^(3.2) denotes a group selected from among

-   -   -   which is optionally substituted by one or more groups            selected from among methyl, ethyl, cyclopentyl, OH, NH₂; or        -   cyclohexyl, which is optionally substituted by one or two            R^(3.2.1)        -   R^(3.2.1) denotes —NR^(3.2.1.1)R^(3.2.1.2) or a group            selected from among

-   -   -   -   or a group selected from among

-   -   -   -   which is optionally substituted by one or more groups                selected from among methyl, SO₂R^(3.2.1.1),

-   -   -   -   R^(3.2.1.1) denotes H, methyl or benzyl;            -   R^(3.2.1.2) denotes H, methyl or benzyl; or —C₁₋₆-alkyl,                straight-chain or branched, which is optionally                substituted by one or two R^(3.2.2);

        -   R^(3.2.2) denotes C═CH₂, C≡CH, COOR^(3.2.2.1),            CONR^(3.2.2.1)R^(3.2.2.2), NR^(3.2.2.1)R^(3.2.2.2),            NHCOR^(3.2.2.1), CF₃, CN, OH, SO₂R^(3.2.2.1) or a group            selected from among

-   -   -   -   or a group selected from among

-   -   -   -   which is optionally substituted by one or more groups                selected from among Cl, methyl,                CONR^(3.2.2.1)R^(3.2.2.2), OH;            -   R^(3.2.2.1) denotes H or methyl;            -   R^(3.2.2.2) denotes H or methyl; or

        -   phenyl, which is optionally substituted by one or two            R^(3.2.3)

        -   R^(3.2.3) denotes a group selected from among

-   -   R^(3.3) denotes H, methyl or ethyl;

-   R^(b) denotes R⁴, CH₂OR⁴, COR⁴, COOR⁴, CONR⁴R⁵, NH₂, NHCOOR⁴,    NHCONR⁴R⁵ or OH;

-   R⁴ denotes H, methyl, ethyl, 2-hydroxyethyl, propyl, C≡CH, CF₃,    phenyl,

-   R⁵ denotes H, methyl or ethyl;-   R^(c) denotes NHR⁶ or a group selected from among

wherein

-   -   B denotes a bond, methylene, ethylene, propylene or butynylene;    -   R⁶ denotes H, phenyl, optionally substituted by SO₂CH₃;    -   R⁷ denotes H, NR^(7.1)R^(7.2), OR^(7.2), SR^(7.2) or a group        selected from among

-   -   R^(7.1) denotes H, methyl, ethyl, (CH₂)₂R^(7.1.1) or COObutyl;    -   R^(7.2) denotes H, methyl or ethyl;        -   R^(7.11) denotes NMe₂ or 1-imidazolyl            and the pharmacologically acceptable salts, diastereomers,            enantiomers, racemates, hydrates or solvates thereof.

Particularly preferred are the above-mentioned compounds of formula 1wherein

-   R^(c) denotes a group

wherein

-   B denotes methylene, propylene;-   R⁷ denotes H, NR^(7.1)R^(7.2) or 1-imidazolyl;    -   R^(7.1) denotes H or methyl;    -   R^(7.2) denotes H or methyl;        and the pharmacologically acceptable salts, diastereomers,        enantiomers, racemates, hydrates or solvates thereof.

Particularly preferred are the above-mentioned compounds of formula 1wherein

-   R^(a) denotes phenyl, optionally substituted by one or more groups    selected from among R¹, R² and R³;    and the pharmacologically acceptable salts, diastereomers,    enantiomers, racemates, hydrates or solvates thereof.

Particularly preferred are the above-mentioned compounds of formula 1wherein

-   R^(a) denotes phenyl, optionally substituted by one or more groups    selected from among R¹ and R³;-   R¹ denotes methyl, ethyl, propyl, CF₃, methoxy, F, Cl or Br;-   R³ denotes a group

and the pharmacologically acceptable salts, diastereomers, enantiomers,racemates, hydrates or solvates thereof.

Particularly preferred are the above-mentioned compounds of formula 1wherein

-   R^(a) denotes phenyl, optionally substituted by one or more groups    selected from among R¹ and R³;-   R¹ denotes methyl, ethyl, propyl, CF₃, methoxy, F, Cl or Br;-   R³ denotes a group

and the pharmacologically acceptable salts, diastereomers, enantiomers,racemates, hydrates or solvates thereof.

Particularly preferred of the above-mentioned compounds of formula 1 arethe compounds of formula 1.1

wherein R^(a), R^(b) and R^(c) have the meanings given above, and thepharmacologically acceptable salts, diastereomers, enantiomers,racemates, hydrates or solvates thereof.

Particularly preferred are the above-mentioned compounds of formula 1.1;wherein

-   R^(a) denotes phenyl, optionally substituted by one or more groups    selected from among R¹, R² and R³; or

-   R¹ denotes methyl, ethyl, propyl, CF₃, CH₂COOH, methoxy, F, Cl, Br,    CN, COR^(1.1) or SO₂R^(1.1);    -   R^(1.1) denotes OH, methyl, NH₂, NHMe, NMe₂ or

-   R² denotes methyl, F, Cl or Br;-   R³ denotes a group selected from among

-   -   wherein    -   n denotes 0 or 1;    -   m denotes 0 or 1;    -   o denotes 2;    -   R^(3.1) denotes a group selected from among

-   -   -   or a group selected from among

-   -   -   which may optionally be substituted by one or more            R^(3.1.1);        -   R^(3.1.1) denotes methyl, OH, CH₂OH, CH₂CH₂OH, CH₂NEt₂,            COMe, COOH, CONH₂,

-   -   R^(3.2) denotes a group selected from among

-   -   -   which is optionally substituted by one or more groups            selected from among methyl, ethyl, cyclopentyl, OH, NH₂; or        -   cyclohexyl, which is optionally substituted by one or two            R^(3.2.1)        -   R^(3.2.1) denotes —NR^(3.2.1.1)R^(3.2.1.2) or a group            selected from among

-   -   -   -   or a group selected from among

-   -   -   -   which is optionally substituted by one or more methyl                groups            -   R^(3.2.1.1) denotes H or methyl;            -   R^(3.2.1.2) denotes H or methyl; or

        -   —C₁₋₆-alkyl, straight-chain or branched, which is optionally            substituted by one or two R^(3.2.2);

        -   R^(3.2.2) denotes C═CH₂, C≡CH, COOR^(3.2.2.1),            CONR^(3.2.2.1)R^(3.2.2.2), NR^(3.2.2.1)R^(3.2.2.2), CN, OH            or a group selected from among

-   -   -   -   or a group selected from among

-   -   -   -   which is optionally substituted by one or more groups                selected from among methyl, CONR^(3.2.2.1)R^(3.2.2.2),                OH;            -   R^(3.2.2.1) denotes H or methyl;            -   R^(3.2.2.2) denotes H or methyl; or

        -   phenyl, which is optionally substituted by one or two            R^(3.2.3)

        -   R^(3.2.3) denotes a group selected from among

-   -   R^(3.3) denotes H, methyl or ethyl;

-   R^(b) R⁴, CH₂OCH₃, COR⁴, COOH, COOCH₃CONR⁴R⁵, NH₂, NHCOOR⁴ or OH;

-   R⁴ denotes H, methyl, propyl, C≡CH, phenyl,

-   R⁵ denotes H or methyl;-   R^(c) denotes a group

wherein

-   B denotes methylene, propylene;-   R⁷ denotes H, NR^(7.1)R^(7.2) or 1-imidazolyl;    -   R^(7.1) denotes H or methyl;    -   R^(7.2) denotes H or methyl;        and the pharmacologically acceptable salts, diastereomers,        enantiomers, racemates, hydrates or solvates thereof.

Most preferred are the above-mentioned compounds of formula 1.1; wherein

-   R^(a) denotes phenyl, optionally substituted by one or more groups    selected from among R¹, R² and R³; or

-   R¹ denotes methyl, CF₃, methoxy, F, Cl, Br, COR^(1.1) or SO₂R^(1.1);    -   R^(1.1) denotes OH, NH₂, NHMe or NMe₂;-   R² denotes Cl;-   R³ denotes a group selected from among

-   -   wherein    -   n denotes 0 or 1;    -   m denotes 0 or 1;    -   R^(3.1) denotes a group selected from among

-   -   -   or a group selected from among

-   -   -   which may optionally be substituted by one or more            R^(3.1.1);        -   R^(3.1.1) denotes OH, CONH₂ or 4-pyridinyl,

    -   R^(3.2) denotes a group selected from among

-   -   -   which is optionally substituted by one or more methyl            groups; or        -   cyclohexyl, which is optionally substituted by one or two            R^(3.2.1)        -   R^(3.2.1) denotes a group selected from among

-   -   -   —C₁₋₆-alkyl, straight-chain or branched, which is optionally            substituted by one or two R^(3.2.2);        -   R^(3.2.2) denotes COOR^(3.2.2.1), CONR^(3.2.2.1)R^(3.2.2.2),            4-pyridinyl or a group selected from among

-   -   -   -   which is optionally substituted by one or more groups                selected from among methyl;            -   R^(3.2.2.1) denotes H or methyl;            -   R^(3.2.2.2) denotes H or methyl; or

    -   R^(3.3) denotes H, methyl or ethyl;

-   R^(b) denotes R⁴, CH₂OCH₃ or OH;

-   R⁴ denotes H, C≡CH,

-   R^(c) denotes a group

wherein

-   B denotes methylene, propylene;-   R⁷ denotes H or NR^(7.1)R^(7.2);    -   R^(7.1) denotes H or methyl;    -   R^(7.2) denotes H or methyl;        and the pharmacologically acceptable salts, diastereomers,        enantiomers, racemates, hydrates or solvates thereof.

Particularly preferred of the above-mentioned compounds of formula 1 arethe compounds of formula 1.2

wherein R^(a), R^(b) and R^(c) have the meanings given above, and thepharmacologically acceptable salts, diastereomers, enantiomers,racemates, hydrates or solvates thereof.

Particularly preferred are the above-mentioned compounds of formula 1.2;wherein R^(b) and R^(c) have the meanings given above and

-   R^(a) denotes aryl, optionally substituted by one or more groups    selected from among R¹, R² and R³;-   R¹ and R² independently of one another denote C₁₋₆-alkyl,    C₁₋₆-haloalkyl, C₁₋₆-alkoxy, halogen, COR^(1.1), SO₂R^(1.1),    -   R^(1.1) denotes C₁₋₆-alkyl, NR^(1.1.1)R^(1.1.2)        -   R^(1.1.1) denotes H, C₁₋₆-alkyl, optionally substituted by a            group selected from among NH₂, NHMe, NMe₂;        -   R^(1.1.2) denotes H, C₁₋₆-alkyl;        -   or R^(1.1.1) and R^(1.1.2) together form a five- or            six-membered heterocyclic ring, which may optionally be            substituted by a group selected from among methyl, ethyl,            propyl;-   R³ denotes a group selected from among

-   -   wherein    -   X denotes a bond or C₁₋₄-alkylene;    -   R^(3a) denotes a group, which may be identical or different,        selected from among R^(3.1), R^(3.2) and R^(3.3);    -   R^(3.1) denotes spiro or het, while het may optionally be        substituted by one or more R^(3.1.1);        -   R^(3.1.1) denotes NR^(3.1.1.1)R^(3.1.1.2);        -   R^(3.1.1.1) denotes H, C₁₋₄-alkyl;        -   R^(3.1.1.2) denotes H, C₁₋₄-alkyl;            and the pharmacologically acceptable salts, diastereomers,            enantiomers, racemates, hydrates or solvates thereof.

Particularly preferred are the above-mentioned compounds of formula 1.2;wherein

-   R^(a) denotes phenyl, optionally substituted by one or more groups    selected from among R¹, R² and R³;-   R¹ and R² independently of one another denote C₁₋₆-alkyl,    C₁₋₆-haloalkyl, C₁₋₆-alkoxy, halogen, COR^(1.1), SO₂R^(1.1),    -   R^(1.1) denotes methyl ethyl, propyl, NR^(1.1.1)R^(1.1.2)        -   R^(1.1.1) denotes H, methyl ethyl, propyl;        -   R^(1.1.2) denotes H, methyl ethyl, propyl;        -   or R^(1.1.1) and R^(1.1.2) together form a five- or            six-membered heterocyclic ring, which may optionally be            substituted by a group selected from among methyl, ethyl,            propyl;-   R³ denotes a group selected from among

-   -   wherein    -   X denotes a bond or methylene, ethylene, propylene;    -   R^(3a) denotes a group, which may be identical or different,        selected from among R^(3.1), R^(3.2) and R^(3.3);    -   R^(3.1) denotes spiro or het, while het may optionally be        substituted by one or more R^(3.11)        -   R^(3.1.1.1) denotes NR^(3.1.11)R^(3.1.1.2)        -   R^(3.1.1.1) denotes H, methyl ethyl, propyl;

-   R^(3.1.1.2) denotes H, methyl ethyl, propyl;

-   R^(b) denotes R⁴;

-   R⁴ denotes H;

-   R^(c) denotes NHR⁶ or a group

wherein

-   B denotes a bond, methylene, ethylene or propylene;-   R⁶ denotes H;-   R⁷ denotes H or NR^(7.1)R^(7.2)

-   -   R^(7.1) denotes H, methyl, ethyl, (CH₂)₂R^(7.1.1) or COObutyl;    -   R^(7.2) denotes H, methyl or ethyl;        -   R^(7.1.1) denotes NMe₂ or 1-imidazolyl            and the pharmacologically acceptable salts, diastereomers,            enantiomers, racemates, hydrates or solvates thereof.

Particularly preferred are the above-mentioned compounds of formula 1.2;wherein

-   R^(a) denotes phenyl, optionally substituted by one or more groups    selected from among R¹ and R²;-   R¹ denotes methyl, ethyl, propyl, CF₃, F, Cl, COR^(1.1) or    SO₂R^(1.1);    -   R^(1.1) denotes methyl;-   R² denotes methyl, F or Cl;-   R^(b) denotes R⁴;-   R⁴ denotes H;-   R^(c) denotes NHR⁶ or a group

wherein

-   B denotes a bond, methylene, ethylene or propylene;-   R⁶ denotes H;-   R⁷ denotes H or NR^(7.1)R^(7.2);

-   -   R^(7.1) denotes H, methyl, ethyl, (CH₂)₂R^(7.1.1) or COObutyl;    -   R^(7.2) denotes H, methyl or ethyl;        -   R^(7.1.1) denotes NMe₂ or 1-imidazolyl            and the pharmacologically acceptable salts, diastereomers,            enantiomers, racemates, hydrates or solvates thereof.

Most preferred are the above-mentioned compounds of formula 1.2; wherein

-   R^(a) denotes phenyl, optionally substituted by R¹;-   R¹ denotes methyl, F, Cl, Br or COR^(1.1);    -   R^(1.1) denotes methyl;-   R^(b) denotes R⁴;-   R⁴ denotes H;-   R^(c) denotes a group

wherein

-   B denotes a bond, methylene or propylene;-   R⁷ denotes H or NR^(7.1)R^(7.2),    -   R^(7.1) denotes H or methyl;    -   R^(7.2) denotes methyl;        and the pharmacologically acceptable salts, diastereomers,        enantiomers, racemates, hydrates or solvates thereof.

Particularly preferred of the above-mentioned compounds of formula 1 arethe compounds of formula 1.3

wherein R^(a), R^(b) and R^(c) have the meanings given above, and thepharmacologically acceptable salts, diastereomers, enantiomers,racemates, hydrates or solvates thereof.

Particularly preferred are the above-mentioned compounds of formula 1.3;wherein R^(b) and R^(c) have the meanings given above and

-   R^(a) denotes aryl, optionally substituted by one or more groups    selected from among R¹, R² and R³, or hetaryl;-   R¹ and R² independently of one another denote C₁₋₆-alkyl,    C₁₋₆-haloalkyl, C₁₋₆-alkoxy, halogen, COR^(1.1);    -   R^(1.1) denotes OH, C₁₋₆-alkyl, NR^(1.1.1)R^(1.1.2)        -   R^(1.1.1) denotes H, C₁₋₆-alkyl, optionally substituted by a            group selected from among NH₂, NHMe, NMe₂;        -   R^(1.1.2) denotes H, C₁₋₆-alkyl;        -   or R^(1.1.1) and R^(1.1.2) together form a five- or            six-membered heterocyclic ring, which may optionally be            substituted by a group selected from among methyl, ethyl,            propyl;-   R³ denotes a group selected from among

-   -   wherein    -   X denotes a bond or C₁₋₄-alkylene;    -   R^(3a) denotes a group, which may be identical or different,        selected from among R^(3.1), R^(3.2) and R^(3.3);    -   R^(3.1) denotes spiro or het, while het may optionally be        substituted by one or more R^(3.1.1);        -   R^(3.1.1) denotes NR^(3.1.1.1)R^(3.1.1.2);            -   R^(3.1.1.1) denotes H, C₁₋₄-alkyl;            -   R^(3.1.1.2) denotes H, C₁₋₄-alkyl;                and the pharmacologically acceptable salts,                diastereomers, enantiomers, racemates, hydrates or                solvates thereof.

Particularly preferred are the above-mentioned compounds of formula 1.3;wherein

-   R^(a) denotes phenyl, optionally substituted by one or more groups    selected from among R¹, R² and R³, pyrazolyl or pyridinyl;-   R¹ and R² independently of one another denote C₁₋₆-alkyl,    C₁₋₆-haloalkyl, C₁₋₆-alkoxy, halogen, COR^(1.1),    -   R^(1.1) denotes methyl ethyl, propyl, NR^(1.1.1)R^(1.1.2)        -   R^(1.1.1) denotes H, methyl ethyl, propyl;        -   R^(1.1.2) denotes H, methyl ethyl, propyl;        -   or R^(1.1.1) and R^(1.1.2) together form a five- or            six-membered heterocyclic ring, which may optionally be            substituted by a group selected from among methyl, ethyl,            propyl;-   R³ denotes a group selected from among

-   -   wherein    -   X denotes a bond or C₁₋₄-alkylene;    -   R^(3a) denotes a group, which may be identical or different,        selected from among R^(3.1), R^(3.2) and R^(3.3)    -   R^(3.1) denotes spiro or het, while het may optionally be        substituted by one or more R^(3.1.1);        -   R^(3.1) denotes NR^(3.1.1.1)R^(3.1.1.2)            -   R^(3.1.1.1) denotes H, methyl ethyl, propyl;            -   R^(3.1.1.2) denotes H, methyl ethyl, propyl;

-   R^(b) denotes R⁴ or OH;

-   R⁴ denotes H;

-   R^(c) denotes NHR⁶ or a group

wherein

-   B denotes a bond, methylene, ethylene or propylene;-   R⁶ denotes H;-   R⁷ denotes H, NR^(7.1)R^(7.2) or a group selected from among

-   -   R^(7.1) denotes H, methyl or (CH₂)₂R^(7.1.1);    -   R^(7.2) denotes H, methyl or ethyl;        -   R^(7.1.1) denotes NMe₂;            and the pharmacologically acceptable salts, diastereomers,            enantiomers, racemates, hydrates or solvates thereof.

Particularly preferred are the above-mentioned compounds of formula 1.3;wherein

-   R^(a) denotes phenyl, optionally substituted by one or more groups    selected from among R¹ and R²; or

-   R¹ denotes methyl, methoxy, Cl, OH or COR^(1.1);    -   R^(1.1) denotes NH₂, NHMe or NMe₂;-   R² denotes methoxy or Cl;-   R^(b) denotes R⁴ or OH;-   R⁴ denotes H;-   R^(c) denotes NHR⁶ or a group

wherein

-   B denotes a bond, methylene, ethylene or propylene;-   R⁶ denotes H;-   R⁷ denotes H, NR^(7.1)R^(7.2) or a group selected from among

-   R^(7.1) denotes H, methyl or (CH₂)₂R^(7.1.1);    -   R^(7.2) denotes H, methyl or ethyl;        -   R^(7.1.1) denotes NMe₂;            and the pharmacologically acceptable salts, diastereomers,            enantiomers, racemates, hydrates or solvates thereof.

Most preferred are the above-mentioned compounds of formula 1.3; wherein

-   R^(a) denotes phenyl, optionally substituted by one or more groups    selected from among R¹, R² and R³; or-   R¹ denotes Cl or COR^(1.1)    -   R^(1.1) denotes NH₂;-   R² denotes Cl;-   R^(b) denotes R⁴ or OH;-   R⁴ denotes H;-   R^(c) denotes NHR⁶ or a group

wherein

-   B denotes methylene;-   R⁶ denotes H;-   R⁷ denotes H;    and the pharmacologically acceptable salts, diastereomers,    enantiomers, racemates, hydrates or solvates thereof.

Particularly preferred of the above-mentioned compounds of formula 1 arethe above-mentioned compounds of formula 1.4

wherein R^(a), R^(b) and R^(c) have the meanings given above, and thepharmacologically acceptable salts, diastereomers, enantiomers,racemates, hydrates or solvates thereof.

Particularly preferred are the above-mentioned compounds of formula 1.4;wherein

-   R^(a) denotes phenyl, optionally substituted by one or more groups    selected from among R¹ and R³; or-   R¹ denotes methyl, F, Cl or Br;-   R³ denotes a group selected from among

-   -   wherein    -   m denotes 0;    -   R^(3.2) denotes a group

-   -   -   which is optionally substituted by a group selected from            among methyl and cyclopentyl;        -   cyclohexyl, which is optionally substituted by a R^(3.2.1)        -   R^(3.2.1) denotes a group

-   -   R^(3.3) denotes H;

-   R^(b) denotes R⁴;

-   R⁴ denotes a group selected from among

-   R^(c) denotes a group    wherein-   B denotes methylene;-   R⁷ denotes H;    and the pharmacologically acceptable salts, diastereomers,    enantiomers, racemates, hydrates or solvates thereof.

Most preferred are the above-mentioned compounds of formula 1.4; wherein

-   R^(a) denotes phenyl, optionally substituted by one or more groups    selected from among R¹ and R³; or-   R¹ denotes Cl;-   R³ denotes a group selected from among

-   -   wherein    -   m denotes 0;    -   R^(3.2) denotes a group

-   -   -   which is optionally substituted by methyl; or        -   cyclohexyl, which is optionally substituted by a R^(3.2.1)        -   R^(3.2.1) denotes a group

-   -   R^(3.3) denotes H;

-   R^(b) denotes R⁴;

-   R⁴ denotes a group

-   R^(c) denotes a group

wherein

-   B denotes methylene;-   R⁷ denotes H;    and the pharmacologically acceptable salts, diastereomers,    enantiomers, racemates, hydrates or solvates thereof.

Also preferred are the above-mentioned compounds of formula 1; wherein

-   R^(a) denotes H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₈-cycloalkyl,    C₃₋₈-cycloalkenyl, C₁₋₆-haloalkyl, COR⁸, NR⁹R¹⁰, NO₂, OR⁸, SR¹¹,    SOR¹¹, SO₂R¹¹, NHCO—C₁₋₆-alkyl-NH₂, spiro or a group selected from    among C₇₋₁₁- aralkyl, CH₂—O-aryl and het which may optionally be    substituted by one or more halogens, C₁₋₆-alkyl, CO—C₁₋₄-haloalkyl,    C₁₋₄-alkyl-NH₂ or CH₂NHCOOR¹²;-   R⁸ denotes C₁₋₆-alkyl, C₃₋₆-cycloalkyl, NH₂, hetaryl or aryl,    optionally substituted by one or more halogens or C₁₋₄-alkyl;-   R⁹ denotes H, COOR¹², CONR¹² or C₁₋₆-alkyl, optionally substituted    by one or more COOH, N(C₁₋₆-alkyl)₂ or het, optionally substituted    by one or more C₁₋₆-alkyl; or R⁹ denotes het, optionally substituted    by one or more C₁₋₄-alkyl;-   R¹⁰ denotes H, C₁₋₆-alkyl, CO—C₁₋₆-alkyl or C₂₋₆-alkynyl;-   R¹¹ denotes C₁₋₆-alkyl, optionally substituted by one or more    N(C₁₋₄-alkyl)₂;-   R¹² denotes H, C₁₋₆-alkyl;-   R^(b) denotes R⁴, OR⁴, —CH₂OR⁴, COR⁴, COOR⁴, CONR⁴R⁵, NR⁴R⁵,    NR⁵COR⁴, NR⁵COOR⁴NR⁵CONR⁴R⁵, NR⁵SOR⁴ or NR⁵SO₂R⁴;-   R⁴, R⁵ denote H, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkylene-OH,    C₂₋₆-alkenyl, C₇₋₁₁-aralkyl, C₂₋₄-alkenyl-aryl, C₂₋₄-alkynyl-aryl,    C₁₋₄-alkyl-hetaryl, C₂₋₄-alkenyl-hetaryl, C₂₋₄-alkynyl-hetaryl,    C₂₋₆-alkynyl, optionally substituted by Si(C₁₋₄-alkyl)₃, or R⁴    denotes a group selected from among aryl, het, hetaryl and    optionally substituted by C₁₋₄-alkyl;    or R⁴ and R⁵ together form a five-, six- or seven-membered ring    consisting of carbon atoms and optionally a heteroatom selected from    among oxygen, nitrogen and sulphur;-   R^(c) denotes NHR⁶ or a group selected from among

wherein

-   B denotes a bond, C₁₋₆-alkyl, C₂₋₆-alkenyl or C₂₋₆-alkynyl;-   R⁶ denotes H or a group selected from among C₁₋₄-alkyl,    C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkenyl, het,    aryl, hetaryl optionally substituted by one or more groups R^(6.1);    -   R^(6.1) denotes halogen, CF₃, OH, CN, OMe, SO₂(C₁₋₄-alkyl);-   R⁷ denotes H, C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl,    C₃₋₆-cycloalkyl, NR^(7.1)R^(7.2), OR^(7.2), SR^(7.2), hetaryl, het,    optionally substituted by C₁₋₄-alkyl or CONH₂;    -   R^(7.1) denotes H, C₁₋₆-alkyl, (CH₂)₂₋₄R^(7.1.1) or COObutyl;    -   R^(7.2) denotes H, C₁₋₆-alkyl, optionally substituted by one or        more OH;        -   R^(7.1.1) denotes NR^(7.1.1.1)R^(7.1.1.2), het or            1-imidazolyl, 2-(N-ethylpyrrolidine);            -   R^(7.1.1.1) denotes H or C₁₋₆-alkyl;            -   R^(7.1.1.2) denotes H or C₁₋₆-alkyl;                and the pharmacologically acceptable salts,                diastereomers, enantiomers, racemates, hydrates or                solvates thereof, with the proviso that R^(a) cannot be                H or Me if Y=nitrogen; Z=nitrogen; j=2; k=0; R^(b)=H and                R^(c)=NHCONH-Et.

Preferred compounds of formula 1 mentioned above are those wherein

-   R^(a) denotes H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₈-cycloalkyl,    C₃₋₈-cycloalkenyl, C₁₋₆-haloalkyl, COR⁸, NR⁹R¹⁰, NO₂, OR⁸, SR¹¹,    SOR¹¹, SO₂R¹¹, NHCO—C₁₋₆-alkyl-NH₂, spiro or a group selected from    among C₇₋₁₁- aralkyl, CH₂—O-aryl and het which may optionally be    substituted by one or more halogens, C₁₋₆-alkyl, CO—C₁₋₄-haloalkyl,    C₁₋₄-alkyl-NH₂ or CH₂NHCOOR¹²;-   R⁸ denotes C₁₋₆-alkyl, C₃₋₆-cycloalkyl, NH₂, hetaryl or aryl,    optionally substituted by one or more halogens or C₁₋₄-alkyl;-   R⁹ denotes H, COOR¹² or C₁₋₄-alkyl, optionally substituted by one or    more COOH, N(C₁₋₄-alkyl)₂ or het, optionally substituted by one or    more C₁₋₄-alkyl; or R⁹ denotes het, optionally substituted by one or    more C₁₋₄-alkyl;-   R¹⁰ denotes H, C₁₋₆-alkyl, CO—C₁₋₄-alkyl or C₂₋₆-alkynyl;-   R¹¹ denotes C₁₋₆-alkyl, optionally substituted by one or more    N(C₁₋₄-alkyl)₂;-   R¹² denotes C₁₋₆-alkyl;-   R^(b) denotes R⁴, OR⁴, —CH₂OR⁴, COR⁴, COOR⁴, CONR⁴R⁵, NR⁴R⁵,    NR⁵COR⁴, NR⁵COOR⁴, NR⁵CONR⁴R⁵, NR⁵SOR⁴ or NR⁵SO₂R⁴;-   R⁴ denotes H, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkylene-OH,    C₂₋₆-alkenyl, C₇₋₁₁-aralkyl, C₂₋₄-alkenyl-aryl, C₂₋₄-alkynyl-aryl,    C₁₋₄-alkyl-hetaryl, C₂₋₄-alkenyl-hetaryl, C₂₋₄-alkynyl-hetaryl,    C₂₋₆-alkynyl, optionally substituted by Si(C₁₋₄-alkyl)₃, or R⁴    denotes a group selected from among aryl, het, hetaryl and    optionally substituted by C₁₋₄-alkyl;-   R⁵ denotes H or C₁₋₆-alkyl;    or R⁴ and R⁵ together form a five-, six- or seven-membered ring    consisting of carbon atoms and optionally a heteroatom selected from    among oxygen, nitrogen and sulphur;-   R^(c) denotes NHR⁶ or a group selected from among

wherein

-   B denotes a bond, C₁₋₄-alkyl or C₂₋₄-alkynyl;-   R⁶ denotes H or a group selected from among C₁₋₄-alkyl,    C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkenyl, het,    aryl, hetaryl optionally substituted by one or more groups R^(6.1);    -   R^(6.1) denotes halogen, CF₃, OH, CN, OMe, SO₂(C₁₋₄-alkyl);-   R⁷ denotes H, C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl,    C₃₋₆-cycloalkyl, NR^(7.1)R^(7.2), OR^(7.2), SR^(7.2), hetaryl, het,    optionally substituted by C₁₋₄-alkyl or CONH₂;    -   R^(7.1) denotes H, C₁₋₄-alkyl, (CH₂)₂₋₄R^(7.1.1) or COObutyl;    -   R^(7.2) denotes H, C₁₋₆-alkyl, optionally substituted by one or        more OH;        -   R^(7.1.1) denotes NR^(7.1.1.1)R^(7.1.1.2), het or            1-imidazolyl, 2-(N-ethylpyrrolidine);            -   R^(7.1.1.1) denotes H or C₁₋₆-alkyl;            -   R^(7.1.1.2) denotes H or C₁₋₆-alkyl;                and the pharmacologically acceptable salts,                diastereomers, enantiomers, racemates, hydrates or                solvates thereof, with the proviso that R^(a) cannot be                H or Me if Y=nitrogen; Z=nitrogen; j=2; k=0; R^(b)=H and                R^(c)=NHCONH-Et.

Preferred compounds of formula 1 mentioned above are those wherein

-   R^(a) denotes H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₆-cycloalkyl,    C₃₋₆-cycloalkenyl, C₁₋₆-haloalkyl, COR⁸, NR⁹R¹⁰, NO₂, OR⁸, SR¹¹,    SOR¹¹, SO₂R¹¹, NHCO—C₁₋₆-alkyl-NH₂, spiro or a group selected from    among C₇₋₁₁- aralkyl, CH₂—O-aryl and het which may optionally be    substituted by one or more halogens, C₁₋₆-alkyl, CO—C₁₋₄-haloalkyl,    C₁₋₄-alkyl-NH₂ or CH₂NHCOOR¹²;-   R⁸ denotes C₁₋₆-alkyl, C₃₋₆-cycloalkyl, NH₂, hetaryl or aryl,    optionally substituted by one or more halogens or C₁₋₄-alkyl;-   R⁹ denotes H, COOR¹² or C₁₋₄-alkyl, optionally substituted by one or    more COOH, N(C₁₋₄-alkyl)₂ or het, optionally substituted by one or    more C₁₋₄-alkyl; or R⁹ denotes het, optionally substituted by one or    more C₁₋₄-alkyl;-   R¹⁰ denotes H, C₁₋₆-alkyl, CO—C₁₋₄-alkyl or C₂₋₆-alkynyl;-   R¹¹ denotes C₁₋₆-alkyl, optionally substituted by one or more    N(C₁₋₄-alkyl)₂;-   R¹² denotes C₁₋₆-alkyl;-   R^(b) denotes R⁴, OR⁴, —CH₂OR⁴, COR⁴, COOR⁴, CONR⁴R⁵, NH₂, NR⁵COOR⁴,    NR⁵CONR⁴R⁵ or NR⁵SOR⁴;-   R⁴ denotes H, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkylene-OH,    C₂₋₆-alkenyl, C₇₋₁₁-aralkyl, C₁₋₄-alkyl-hetaryl, C₂₋₆-alkynyl,    optionally substituted by Si(C₁₋₄-alkyl)₃, or R⁴ denotes a group    selected from among aryl, het, hetaryl and optionally substituted by    C₁₋₄-alkyl;-   R⁵ denotes H or C₁₋₆-alkyl;-   or R⁴ and R⁵ together form a five-, six- or seven-membered ring    consisting of carbon atoms and optionally a heteroatom selected from    among oxygen, nitrogen and sulphur;-   R^(c) denotes NHR⁶ or a group selected from among

wherein

-   B denotes a bond, C₁₋₄-alkyl or C₂₋₄-alkynyl;-   R⁶ denotes H or a group selected from among C₁₋₄-alkyl,    C₃₋₆-cycloalkyl, het, aryl, hetaryl optionally substituted by one or    more groups R^(6.1);    -   R^(6.1) denotes halogen, CF₃, OH, CN, OMe, SO₂(C₁₋₄-alkyl);-   R⁷ denotes H, C₁₋₄-alkyl, C₃₋₆-cycloalkyl, NR^(7.1)R^(7.2),    OR^(7.2), SR^(7.2), hetaryl, het, optionally substituted by    C₁₋₄-alkyl or CONH₂;    -   R^(7.1) denotes H, C₁₋₄-alkyl, (CH₂)₂₋₄R^(7.1.1) or COObutyl;    -   R^(7.2) denotes H, C₁₋₆-alkyl, optionally substituted by one or        more OH;        -   R^(7.1.1) denotes NR^(7.1.1.1)R^(7.1.1.2), het or            1-imidazolyl, 2-(N-ethylpyrrolidine);            -   R^(7.1.1.1) denotes H or C₁₋₆-alkyl;            -   R^(7.1.1.2) denotes H or C₁₋₆-alkyl;                and the pharmacologically acceptable salts,                diastereomers, enantiomers, racemates, hydrates or                solvates thereof, with the proviso that R^(a) cannot be                H or Me if Y=nitrogen; Z=nitrogen; j=2; k=0; R^(b)=H and                R^(c)=NHCONH-Et.

Preferred compounds of formula 1 mentioned above are those wherein

-   R^(a) denotes H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₆-cycloalkyl, CF₃,    COR⁸, NR⁹R¹⁰, NO₂, S(O)_(n)R¹¹, or a group selected from among

-   -   or a group selected from among

-   -   which may optionally be substituted by one or more Cl;    -   or a group selected from among

-   -   which may optionally be substituted by one or more CH₃, COCF₃,        CH₂NH₂ or CH₂NHCOOR¹²;

-   R⁸ denotes C₁₋₄-alkyl, C₃₋₆-cycloalkyl, NH₂, furanyl or phenyl,    optionally substituted by one or more chlorine;

-   R⁹ denotes H, COOR¹² or piperidino, optionally substituted by one or    more CH₃, or a group selected from among C₁₋₄-alkyl, which may    optionally be substituted by one or more COOH, NMe₂ or    4-methylpiperazine;

-   R¹⁰ denotes H, C₁₋₄-alkyl, C₂₋₄-alkynyl or COCH₃;

-   R¹¹ denotes C₁₋₄-alkyl, optionally substituted by one or more NMe₂,

-   R¹² denotes C₁₋₄-alkyl;

-   R^(b) denotes R⁴, CH₂OR⁴, COR⁴, COOR⁴, CONR⁴R⁵, NH₂, NHCOOR⁴,    NHCONR⁴R⁵ or OH;

-   R⁴ denotes H, C₁₋₄-alkyl, C₁₋₄-alkylene-OH, C₂₋₄-alkynyl,    C₁₋₆-haloalkyl, aryl, het, hetaryl,

-   R⁵ denotes H or C₁₋₄-alkyl;-   R^(c) denotes NHR⁵ or a group selected from among

wherein

-   B denotes a bond, C₁₋₄-alkyl or C₂₋₄-alkynyl;-   R⁶ denotes H, C₁₋₄-alkyl, C₃₋₆-cycloalkyl, C₇₋₁₁- aralkyl, aryl,    optionally substituted by SO₂CH₃;-   R⁷ denotes H, NR^(7.1)R^(7.2), OR^(7.2), SR^(7.2), hetaryl, het,    optionally substituted by C₁₋₄-alkyl or CONH₂, or a group selected    from among

-   -   R^(7.1) denotes H, C₁₋₄-alkyl, (CH₂)₂R^(7.1.1) or COObutyl;    -   R^(7.2) denotes H, C₁₋₄-alkyl;        -   R^(7.1.1) denotes NR^(7.1.1.1)R^(7.1.1.2), het or            1-imidazolyl, 2-(N-ethylpyrrolidine);            -   R^(7.1.1.1) denotes H or C₁₋₆-alkyl;            -   R^(7.1.1.2) denotes H or C₁₋₆-alkyl;                and the pharmacologically acceptable salts,                diastereomers, enantiomers, racemates, hydrates or                solvates thereof, with the proviso that R^(a) cannot be                H or Me if Y=nitrogen; Z=nitrogen; j=2; k=0; R^(b)=H and                R^(c)=NHCONH-Et.

Particularly preferred are the above-mentioned compounds of formula 1wherein

-   R^(a) denotes H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₆-cycloalkyl,    C₃₋₆-cycloalkenyl, CF₃, COR⁸, NR⁹R¹⁰, NO₂, S(O)_(n)R¹¹, spiro,    NHCO—C₁₋₆-alkyl-NH₂ or a group selected from among C₇₋₁₁-aralkyl and    CH₂O-aryl, which may optionally be substituted by one or more Cl; or    a group selected from among het, which may optionally be substituted    by one or more C₁₋₄-alkyl, COCF₃, CH₂NH₂ or CH₂NHCOOR¹²;-   R⁸ denotes C₁₋₄-alkyl, C₃₋₆-cycloalkyl, NH₂, hetaryl, aryl,    optionally substituted by one or more chlorine;-   R⁹ denotes H, COOR¹² or het, optionally substituted by one or more    C₁₋₄-alkyl, or a group selected from among C₁₋₄-alkyl, which may    optionally be substituted by one or more COOH, N(C₁₋₄-alkyl)₂ or    4-methylpiperazine;-   R¹⁰ denotes H, C₁₋₄-alkyl, C₂₋₄-alkynyl or COCH₃;-   R¹¹ denotes C₁₋₄-alkyl, optionally substituted by one or more    N(C₁₋₄-alkyl)₂,-   R¹² denotes C₁₋₄-alkyl;-   n denotes 0 or 2;-   R^(b) denotes H, OH or COOEt;-   R^(c) denotes NH₂ or NHCOR¹³;-   R¹³ denotes C₁₋₄-alkyl, or NR^(13.1)R^(13.2),    -   R^(13.1) denotes H or C₁₋₄-alkyl;    -   R^(13.2) denotes H or C₁₋₄-alkyl;        and the pharmacologically acceptable salts, diastereomers,        enantiomers, racemates, hydrates or solvates thereof, with the        proviso that R^(a) cannot be H or Me if Y=nitrogen; Z=nitrogen;        j=2; k=0; R^(b)=H and R^(c)=NHCONH-Et.

Particularly preferred are the above-mentioned compounds of formula 1wherein

-   R^(a) denotes H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₆-cycloalkyl, CF₃,    COR⁸, NR⁹R¹⁰, NO₂, S(O)_(n)R¹¹, or a group selected from among

-   -   or a group selected from among

-   -   which may optionally be substituted by one or more Cl;    -   or a group selected from among

-   -   which may optionally be substituted by one or more CH₃, COCF₃,        CH₂NH₂ or CH₂NHCOOR¹²;

-   R⁸ denotes C₁₋₄-alkyl, C₃₋₆-cycloalkyl, NH₂, furanyl or phenyl,    optionally substituted by one or more chlorine;

-   R⁹ denotes H, COOR¹² or piperidino, optionally substituted by one or    more CH₃, or a group selected from among C₁₋₄-alkyl, which may    optionally be substituted by one or more COOH, NMe₂ or    4-methylpiperazine;

-   R¹⁰ denotes H, C₁₋₄-alkyl, C₂₋₄-alkynyl or COCH₃;

-   R¹¹ denotes C₁₋₄-alkyl, optionally substituted by one or more NMe₂,

-   R¹² denotes C₁₋₄-alkyl;

-   R^(b) denotes H, OH or COOEt;

-   R^(c) denotes NH₂ or NHCOR¹³;

-   R¹³ denotes C₁₋₄-alkyl, or NR^(13.1)R^(13.2),    -   R^(13.1) denotes H or C₁₋₄-alkyl;    -   R^(13.2) denotes H or C₁₋₄-alkyl;        and the pharmacologically acceptable salts, diastereomers,        enantiomers, racemates, hydrates or solvates thereof, with the        proviso that R^(a) cannot be H or Me if Y=nitrogen; Z=nitrogen;        j=2; k=0; R^(b)=H and R^(c)=NHCONH-Et.

Particularly preferred are the above-mentioned compounds of formula 1wherein

-   R^(a) denotes H, methyl, ethyl, propyl, butyl, 3-methyl-butyl,    propenyl, cyclopropyl, cyclohexyl, CF₃, COR⁸, NR⁹R¹⁰, NO₂,    S(O)_(n)R¹¹, or a group selected from among

-   -   or a group selected from among

-   -   which may optionally be substituted by one or more Cl;    -   or a group selected from among

-   -   which may optionally be substituted by one or more CH₃, COCF₃,        CH₂NH₂ or CH₂NHCOOR¹²;

-   R⁸ denotes methyl, propyl, cyclopropyl, NH₂, furanyl or phenyl,    optionally substituted by one or more chlorine;

-   R⁹ denotes H, COOR¹² or piperidino, optionally substituted by one or    more CH₃, or a group selected from among methyl, ethyl and propyl,    which may optionally be substituted by one or more COOH, NMe₂ or    4-methylpiperazine;

-   R¹⁰ denotes H, methyl, COCH₃, C≡CH or CH₂C≡CH;

-   R¹¹ denotes ethyl or propyl, optionally substituted by one or more    NMe₂,

-   R¹² denotes butyl

-   R^(b) denotes H, OH or COOEt;

-   R^(c) denotes NH₂ or NHCOR¹³;

-   R¹³ denotes methyl or NR^(13.1)R^(13.2),    -   R^(13.1) denotes H or methyl;    -   R^(13.2) denotes H or methyl.        and the pharmacologically acceptable salts, diastereomers,        enantiomers, racemates, hydrates or solvates thereof, with the        proviso that R^(a) cannot be H or Me if Y=nitrogen; Z=nitrogen;        j=2; k=0; R^(b)=H and R^(c)=NHCONH-Et.

Most preferred are the above-mentioned compounds of formula 1; wherein

-   R^(a) denotes propyl, COR⁸, NR⁹R¹⁰, S(O)_(n)R¹¹ and

-   R⁸ denotes furanyl;-   R⁹ denotes methyl;-   R¹⁰ denotes methyl;-   R¹¹ denotes ethyl;-   n denotes 0;-   R^(b) denotes H or OH;-   R^(c) denotes NH₂ or NHCOCH₃;    and the pharmacologically acceptable salts, diastereomers,    enantiomers, racemates, hydrates or solvates thereof.

Particularly preferred are the above compounds, and alsopharmacologically acceptable salts, diastereomers, enantiomers,racemates, hydrates or solvates thereof, with the proviso that R^(a)cannot be H or Me if Y and Z=nitrogen; j=2; k=0; R^(b)=H andR^(c)=NHCONH-Et denotes and that R^(c) cannot be NH₂ if Y andZ=nitrogen; j=2; k=1; R^(b)=H and R^(a)=

Terms and Definitions Used

By the term “C₁₋₆-alkyl” (including those which are part of othergroups) are meant branched and unbranched alkyl groups with 1 to 6carbon atoms, and by the term “C₁₋₄-alkyl” are meant branched andunbranched alkyl groups with 1 to 4 carbon atoms. Alkyl groups with 1 to4 carbon atoms are preferred. Examples of these include: methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,n-pentyl, iso-pentyl, neo-pentyl or hexyl. The abbreviations Me, Et,n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. may optionally also be used for theabove-mentioned groups. Unless stated otherwise, the definitions propyl,butyl, pentyl and hexyl include all the possible isomeric forms of thegroups in question. Thus, for example, propyl includes n-propyl andiso-propyl, butyl includes iso-butyl, sec-butyl and tert-butyl etc.

By the term “C₁₋₆-alkylene” (including those which are part of othergroups) are meant branched and unbranched alkylene groups with 1 to 6carbon atoms and by the term “C₁₋₄-alkylene” are meant branched andunbranched alkylene groups with 1 to 4 carbon atoms. Alkylene groupswith 1 to 4 carbon atoms are preferred. Examples include: methylene,ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene,1,1-dimethylethylene, 1,2-dimethylethylene, pentylene,1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene,1,3-dimethylpropylene or hexylene. Unless stated otherwise, thedefinitions propylene, butylene, pentylene and hexylene also include allthe possible isomeric forms of the relevant groups with the same numberof carbons. Thus for example propyl also includes 1-methylethylene andbutylene includes 1-methylpropylene, 1,1-dimethylethylene,1,2-dimethylethylene.

The term “C₂₋₆-alkenyl” (including those which are part of other groups)denotes branched and unbranched alkenyl groups with 2 to 6 carbon atomsand the term “C₂₋₄-alkenyl” denotes branched and unbranched alkenylgroups with 2 to 4 carbon atoms, provided that they have at least onedouble bond. Preferred are alkenyl groups with 2 to 4 carbon atoms.Examples include: ethenyl or vinyl, propenyl, butenyl, pentenyl, orhexenyl. Unless otherwise stated, the definitions propenyl, butenyl,pentenyl and hexenyl include all possible isomeric forms of the groupsin question. Thus, for example, propenyl includes 1-propenyl and2-propenyl, butenyl includes 1-, 2- and 3-butenyl, 1-methyl-1-propenyl,1-methyl-2-propenyl etc.

By the term “C₂₋₆-alkenylene” (including those which are part of othergroups) are meant branched and unbranched alkenylene groups with 2 to 6carbon atoms and by the term “C₂₋₄-alkenylene” are meant branched andunbranched alkylene groups with 2 to 4 carbon atoms. Alkenylene groupswith 2 to 4 carbon atoms are preferred. Examples include: ethenylene,propenylene, 1-methylethenylene, butenylene, 1-methylpropenylene,1,1-dimethylethenylene, 1,2-dimethylethenylene, pentenylene,1,1-dimethylpropenylene, 2,2-dimethylpropenylene,1,2-dimethylpropenylene, 1,3-dimethylpropenylene or hexenylene. Unlessstated otherwise, the definitions propenylene, butenylene, pentenyleneand hexenylene include all the possible isomeric forms of the respectivegroups with the same number of carbons. Thus, for example, propenyl alsoincludes 1-methylethenylene and butenylene includes 1-methylpropenylene,1,1-dimethylethenylene, 1,2-dimethylethenylene.

By the term “C₂₋₆-alkynyl” (including those which are part of othergroups) are meant branched and unbranched alkynyl groups with 2 to 6carbon atoms and by the term “C₂₋₄-alkynyl” are meant branched andunbranched alkynyl groups with 2 to 4 carbon atoms, provided that theyhave at least one triple bond. Alkynyl groups with 2 to 4 carbon atomsare preferred. Examples include: ethynyl, propynyl, butynyl, pentynyl,or hexynyl. Unless stated otherwise, the definitions propynyl, butynyl,pentynyl and hexynyl include all the possible isomeric forms of therespective groups. Thus, for example, propynyl includes 1-propynyl and2-propynyl, butynyl includes 1-, 2- and 3-butynyl, 1-methyl-1-propynyl,1-methyl-2-propynyl etc.

By the term “C₂₋₆-alkynylene” (including those which are part of othergroups) are meant branched and unbranched alkynylene groups with 2 to 6carbon atoms and by the term “C₂₋₄-alkynylene” are meant branched andunbranched alkylene groups with 2 to 4 carbon atoms. Alkynylene groupswith 2 to 4 carbon atoms are preferred. Examples include: ethynylene,propynylene, 1-methylethynylene, butynylene, 1-methylpropynylene,1,1-dimethylethynylene, 1,2-dimethylethynylene, pentynylene,1,1-dimethylpropynylene, 2,2-dimethylpropynylene,1,2-dimethylpropynylene, 1,3-dimethylpropynylene or hexynylene. Unlessstated otherwise, the definitions propynylene, butynylene, pentynyleneand hexynylene include all the possible isomeric forms of the respectivegroups with the same number of carbons. Thus for example propynyl alsoincludes 1-methylethynylene and butynylene includes 1-methylpropynylene,1,1-dimethylethynylene, 1,2-dimethylethynylene.

By the term “C₁₋₆-alkoxy” (including those which are part of othergroups) are meant branched and unbranched alkoxy groups with 1 to 6carbon atoms and by the term “C₁₋₄-alkoxy” are meant branched andunbranched alkoxy groups with 1 to 4 carbon atoms. Alkoxy groups with 1to 4 carbon atoms are preferred. Examples include: methoxy, ethoxy,propoxy, butoxy or pentoxy. The abbreviations OMe, OEt, OPr, etc. mayoptionally be used for the above-mentioned groups. Unless statedotherwise, the definitions propoxy, butoxy and pentoxy include all thepossible isomeric forms of the respective groups. Thus for examplepropoxy includes n-propoxy and iso-propoxy, butoxy includes iso-butoxy,sec-butoxy and tert-butoxy etc.

By the term “C₃₋₈-cycloalkyl” (including those which are part of othergroups) are meant cyclic alkyl groups with 3 to 8 carbon atoms, by theterm “C₃₋₆-cycloalkyl” are meant cyclic alkyl groups with 3 to 8 carbonatoms and by the term “C₅₋₆-cycloalkyl” are meant cyclic alkyl groupswith 5 to 6 carbon atoms. Examples include: cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. By the term“C₃₋₆-cycloalkenyl” (including those which are part of other groups) aremeant cyclic alkyl groups with 5 or 6 carbon atoms which contain one ortwo double bonds. Examples include: cyclopentenyl, cyclopentadienyl,cyclohexenyl or cyclohexadienyl.

By the term “C₁₋₆-haloalkyl” (including those which are part of othergroups) are meant branched and unbranched alkyl groups with 1 to 6carbon atoms wherein one or more hydrogen atoms are replaced by ahalogen atom selected from among fluorine, chlorine or bromine,preferably fluorine and chlorine, particularly preferably fluorine. Bythe term “C₁₋₄-haloalkyl” are meant correspondingly branched andunbranched alkyl groups with 1 to 4 carbon atoms, wherein one or morehydrogen atoms are replaced analogously to what was stated above.C₁₋₄-haloalkyl is preferred. Examples include: CH₂F, CHF₂, CF₃,

By the term “C₇₋₁₁-aralkyl” (including those which are part of othergroups) are meant branched and unbranched alkyl groups with 1 to 4carbon atoms which are substituted by an aromatic ring system with 6carbon atoms. Examples include: benzyl, 1- or 2-phenylethyl. Unlessotherwise stated, the aromatic groups may be substituted by one or moregroups selected from among methyl, ethyl, iso-propyl, tert-butyl,hydroxy, fluorine, chlorine, bromine and iodine.

By the term “aryl” (including those which are part of other groups) aremeant aromatic ring systems with 6 or 10 carbon atoms. Examples include:phenyl or naphthyl, the preferred aryl group being phenyl.

By the term heterocyclic rings (“het”) are meant five-, six- orseven-membered, saturated or unsaturated heterocyclic rings or 5-10membered, bicyclic heterorings which may contain one, two or threeheteroatoms, selected from among oxygen, sulphur and nitrogen; the ringmay be linked to the molecule by a carbon atom or, if present, by anitrogen atom. The following are examples of five-, six- orseven-membered, saturated or unsaturated heterocyclic rings:

Unless stated otherwise, a heterocyclic ring may be provided with a ketogroup. Examples include:

Examples of 5-10-membered bicyclic heterorings are pyrrolizine, indole,indolizine, isoindole, indazole, purine, quinoline, isoquinoline,benzimidazole, benzofuran, benzopyran, benzothiazole, benzoisothiazole,pyridopyrimidine, pteridine, pyrimidopyrimidine,

Although the term heterocyclic rings includes (“hetaryl”), the termheterocyclic aromatic groups denotes five- or six-membered heterocyclicaromatic groups or 5-10 membered, bicyclic hetaryl rings which maycontain one, two or three heteroatoms, selected from among oxygen,sulphur and nitrogen, which contain sufficient conjugated double bondsthat an aromatic system is formed. The ring may be linked to themolecule through a carbon atom or if present through a nitrogen atom.The following are examples of five- or six-membered heterocyclicaromatic groups:

Examples of 5-10-membered bicyclic hetaryl rings include pyrrolizine,indole, indolizine, isoindole, indazole, purine, quinoline,isoquinoline, benzimidazole, benzofuran, benzopyran, benzothiazole,benzoisothiazole, pyridopyrimidine, pteridine, pyrimidopyrimidine.

By the term heterocyclic spiro rings (“spiro”) are meant 5-10 membered,spirocyclic rings which may optionally contain one, two or threeheteroatoms, selected from among oxygen, sulphur and nitrogen, while thering may be connected to the molecule via a carbon atom or, if present,via a nitrogen atom. Unless otherwise stated, a spirocyclic ring may beprovided with a keto group. Examples include:

By the term “optionally substituted” is meant within the scope of theinvention the above-mentioned group, optionally substituted by alower-molecular group. Examples of lower-molecular groups regarded aschemically meaningful are groups consisting of 1-200 atoms. Preferablysuch groups have no negative effect on the pharmacological efficacy ofthe compounds.

For example the groups may comprise:

-   -   Straight-chain or branched carbon chains, optionally interrupted        by heteroatoms, optionally substituted by rings, heteroatoms or        other common functional groups.    -   Aromatic or non-aromatic ring systems consisting of carbon atoms        and optionally heteroatoms, which may in turn be substituted by        functional groups.    -   A number of aromatic or non-aromatic ring systems consisting of        carbon atoms and optionally heteroatoms which may be linked by        one or more carbon chains, optionally interrupted by        heteroatoms, optionally substituted by heteroatoms or other        common functional groups.

SYNTHESIS OF THE REAGENTSIMIDAZOL-1-YL-[1-(2-TRIMETHYLSILANYL-ETHOXYMETHYL)-1H-IMIDAZOL-4-YL]-METHANONE

A suspension of 1.5 g (63 mmol) sodium hydride (60% suspension inmineral oil) in 80 ml DMF is combined batchwise with 8 g (63 mmol)methyl imidazole-4-carboxylate and the resulting solution is stirred for1 hour. The reaction mixture is cooled to 5° C. and 12 ml (70 mmol)[2-(trimethylsilyl)-ethoxy]methyl chloride are added. After 12 hours thesuspension is combined with 100 ml of water and extracted with ethylacetate. The combined organic phases are washed with sodium chloridesolution, dried and evaporated down.

Yield: 16 g

16 g (62 mmol) of the intermediate described above is dissolved in 20 mldioxane and 66 ml 2 N sodium hydroxide solution and refluxed for 1.5hours. The reaction mixture is acidified with 2 N hydrochloric acid andthe precipitated solid is suction filtered, washed with water anddiethyl ether and dried.

Yield: 13 g

13 g (55 mmol) of the intermediate described above are placed in 150 mldichloromethane and combined with 22.4 g (138 mmol) carbonyldiimidazole.The reaction mixture is stirred for 1 hour at ambient temperature andthen washed with semisaturated sodium chloride solution. The organicphase is dried and evaporated to dryness. Yield: 15 g

IMIDAZOL-1-YL(1-METHYL-1HIMIDAZOL-4-YL)-METHANONE

39.5 g (0.31 mol) 1-methyl-1H-imidazol-4-carboxylic acid are placed in400 ml dichloromethane and 115.6 g (0.71 mol) carbonyldiimidazole areadded. The suspension is stirred for 3 hours at ambient temperature,then extracted with saturated sodium chloride solution. The aqueousphase is extracted with dichloromethane, the combined organic phases aredried and evaporated to dryness. Yield: 60.6 g

1-IMIDAZOL-1-YL-2-METHYL-PROPAN-1-ONE

12.0 g (0.18 mol) imidazole are placed in 200 ml chloroform at 0° C. andthen combined with 10.8 ml (0.10 mol) isobutyl chloride. The mixture isstirred for 1 hour at ambient temperature. Then the reaction mixture iswashed with water, the organic phase is dried and evaporated to dryness.Yield: 10.7 g

(R)-IMIDAZOL-1-YL-(TETRAHYDROFURAN-2-YL)-METHANONE

21.8 g (32 mmol) imidazole are placed in 400 ml chloroform and cooled to0° C. 21.3 g (15.0 mol) (R)-tetrahydrofuran-2-carbonyl chloride areadded dropwise, then the mixture is stirred for 1.5 hours at ambienttemperature. After cooling again to 0° C. the reaction mixture isextracted with semisaturated sodium chloride solution. The organic phaseis dried and evaporated to dryness. Yield: 24.0 g

(S)-IMIDAZOL-1-YL-(TETRAHYDROFURAN-2-YL)-METHANONE

21.8 g (32.0 mmol) imidazole are placed in 400 ml chloroform and cooledto 0° C. 21.5 g (15.0 mmol) (S)-tetrahydrofuran-2-carbonyl chloride areadded dropwise, then stirred for 1.5 hours at ambient temperature. Aftercooling again to 0° C. the reaction mixture is extracted withsemisaturated sodium chloride solution. The organic phase is dried andevaporated to dryness. Yield: 23.5 g

1-IMIDAZOL-1-YL-2-METHOXY-ETHANONE

Analogously to the method described above 5.6 g of the desired productare obtained from 14.9 g (219 mmol) imidazole and 10 ml (109 mmol)methoxyacetic acid chloride.

1-IMIDAZOL-1-YL-3-TRIMETHYLSILANYL-PROPYNONE

0.5 g (3.5 mmol) 3-trimethylsilylpropynoic acid are dissolved in 10 mlTHF and combined with 1.7 g (10.6 mmol) carbonyldiimidazole. Thereaction mixture is stirred overnight at ambient temperature and thenfiltered. The filtrate is diluted with diethyl ether and washed twicewith cold water. The organic phase is dried over magnesium sulphate andevaporated down. Yield: 0.4 g

(4-HYDRAZINO-PHENYL)-ACETIC ACID HYDROCHLORIDE

15.1 g (10.0 mmol) 4-aminophenylacetic acid are placed in a solution of10.6 g (10.0 mmol) sodium carbonate in 100 ml of water. The mixture iscooled to 0° C., then 6.9 g (10.0 mmol) sodium nitrite in 50 ml of waterare added. This mixture is added dropwise to 100 ml of conc.hydrochloric acid while being cooled, then stirred for 0.1 hours. 45.1 g(20.0 mmol) tin(II)-chloride in 40 ml of conc. hydrochloric acid areadded dropwise with vigorous stirring, during which time a precipitateis formed. The reaction mixture is stirred for 1 hour at ambienttemperature, then suction filtered. The precipitate is washed with waterand dried. Yield: 22.0 g

3-CHLORO-5-HYDRAZINO-PHENOL

2.1 g (14.3 mmol) 3-amino-5-chloro-phenol are dissolved in 20 ml ofconc. hydrochloric acid and 20 ml of water and cooled to 0° C. 1.0 g(15.0 mmol) sodium nitrite in 4 ml of water are added. Then a solutionof 12.1 g (53.5 mmol) tin(II)-chloride in 16 ml hydrochloric acid isslowly added dropwise at −5° C. It is stirred for 1 hour at 0° C., thenadjusted to pH7 with sodium hydrogen carbonate. The precipitate formedis suction filtered and washed with water. The filtrate is extractedwith diethyl ether. The organic phase is dried and evaporated todryness. The residue is extracted with hexane.

Yield: 1.2 g

CHLORO-4-HYDRAZINO-PHENOL

analogously to the method described above 2.3 g hydrazine are obtainedfrom 2.2 g (15 mmol) 4-amino-2-chloro-phenol.

METHYL 3-CHLORO-4-HYDRAZINO-BENZOATE

3.0 g (16.0 mmol) methyl-4-amino-3-chlorobenzoate are suspended in 15 mlof conc. hydrochloric acid and cooled to −10° C. First a solution of 1.1g (16.0 mmol) sodium nitrite in 15 ml of water is added dropwise, then asolution of 16.1 g (71.0 mmol) tin(II)-chloride in 13.5 ml hydrochloricacid. A precipitate settles out. The reaction mixture is made basic with3 molar sodium hydroxide solution, then suction filtered. Theprecipitate is extracted with dichloromethane and water, the organicphase is dried, combined with activated charcoal and evaporated todryness. The residue is purified by chromatography. Yield: 1.4 g (M.p.:120° C.)

CHLORO-4-HYDRAZINO-BENZOIC ACID

4.0 g (20.0 mmol) methyl 3-chloro-4-hydrazino-benzoate are taken and 75ml 3 molar sodium hydroxide solution are added thereto. This is stirredfor 16 hours at ambient temperature. Then the reaction mixture isadjusted to pH 6 with glacial acetic acid and the precipitated solid issuction filtered. This is extracted with diethyl ether. Yield: 2.4 g

(4-BROMO-2-TRIFLUOROMETHYL-PHENYL)-HYDRAZINE

A suspension of 25.6 g (0.11 mol) 4-bromo-2-(trifluoromethyl)-aniline in125 ml of conc. hydrochloric acid is cooled to −10° C. and a solution of7.7 g (0.11 mol) sodium nitrite in 125 ml of water is added. Thereaction mixture is stirred for 3 hours at −10 to −5° C., then asolution of 103 g (0.46 mol) tin-(II)-chloride-dihydrate in 125 ml ofconc. hydrochloric acid is added dropwise. The mixture is stirred for 1hour at −5° C. The precipitate formed is suction filtered and washedwith water. The aqueous mother liquor is extracted with petroleum ether,then made basic with sodium hydroxide. The precipitate formed isextracted with diethyl ether. The organic phase is dried and evaporatedto dryness. Yield: 12.9 g

2,2,2-TRIFLUORO-1-(4-HYDRAZINO-PIPERIDIN-1-YL)-ETHANONE-TRIFLUOROACETATE

100 g (0.65 mol) 4-piperidinone-hydrate-hydrochloride and 274.6 ml (1.97mol) triethylamine are placed in 1000 ml dichloromethane and then cooledto 0° C. 182.1 ml (1.31 mol) trifluoroacetic anhydride are slowly addedand the mixture is stirred for 0.5 hours. The reaction mixture is washedwith water and sodium bicarbonate solution, the organic phase is driedand evaporated to dryness. The residue is stirred withmethyl-tert-butylether, the precipitate is suction filtered, washed anddried. Yield: 106.0 g

106.0 g (0.54 mol) 1-(2,2,2-trifluoro-acetyl)-piperidin-4-one aredissolved in 1000 ml of ethanol and combined with 71.8 g (0.54 mol)tert-butyl hydrazinoformate. The reaction mixture is stirred for 3.5hours at ambient temperature, then evaporated to dryness. Yield: 172.0 g

172.0 g (0.56 mol) tert-butylN′-[1-(2,2,2-trifluoro-acetyl)-piperidin-4-ylidene]-hydrazine-carboxylateare dissolved in 2000 ml of methanol. 17.0 g palladium on charcoal (10%)are added and the mixture is hydrogenated at 1 bar hydrogen. After thehydrogen uptake has ended the catalyst is suction filtered and themother liquor concentrated by evaporation. The residue crystallises outovernight. Yield: 168.0 g

5.0 g (16.1 mmol) tert-butylN′-[1-(2,2,2-trifluoro-acetyl)-piperidin-4-yl]-hydrazine-carboxylate aredissolved in 50 ml dichloromethane and combined with 6.0 ml (77.9 mmol)trifluoroacetic acid. The reaction mixture is stirred for 5 hours atambient temperature, then concentrated by evaporation. Yield: 6.70 g

4-(4-METHYL-PIPERAZIN-1-YL)-PHENYLAMINE

18.1 g (0.18 mol) 1-methyl-piperazine, 25.5 g (0.18 mol)1-fluoro-4-nitrobenzene and 50 g (0.36 mol) potassium carbonate areplaced in 200 ml of dimethylformamide and stirred for 15 hours at 130°C. After cooling 300 ml of water are added, during which time aprecipitate is formed. The aqueous phase with the precipitate is cooled,then suction filtered and washed with water. The precipitate isrecrystallised from ethanol.

Yield: 23.2 g

10.0 g (45 mmol) 1-methyl-4-(4-nitro-phenyl)-piperazine are dissolved in250 ml of ethanol, then combined with 2 g palladium/charcoal (10%) andhydrogenated at 5 bar hydrogen for 2 hours. Then the reaction mixture issuction filtered and the filtrate is concentrated by evaporation. Theresidue is recrystallised from cyclohexane. Yield: 7.7 g

4-(1-METHYL-PIPERIDIN-4-YL)-PHENYLAMINE

125 g (0.78 mol) 4-phenylpiperidine are dissolved in 1300 mldichloromethane and combined with 149 ml (0.85 mol)diisopropylethylamine. The reaction mixture is cooled to −5° C., thenwithin 2 hours 120 ml (0.85 mol) trifluoroacetic anhydride are addeddropwise. The mixture is then stirred for 1 hour while cooling with iceand for 16 hours at ambient temperature. 400 ml of water are added andthe phases are separated. The organic phase is washed with water, driedand evaporated to dryness. Yield: 193 g

80 g (0.31 mol) 2,2,2-trifluoro-1-(4-phenyl-piperidin-1-yl)-ethanone aredissolved in 400 ml glacial acetic acid and 200 ml acetic anhydride andcooled to 0° C. 1.6 g sodium nitrite are added, then 52 ml (1.24 mol)fuming nitric acid are added dropwise. The reaction mixture is stirredfor 16 hours at ambient temperature. Then the reaction mixture is pouredonto 1200 ml ice water and adjusted to pH 8 with 8 N sodium hydroxidesolution (temp. <20° C.). After the addition of dichloromethane thephases are separated and the aqueous phase is extracted withdichloromethane. The combined organic phases are washed with 0.1 Nsodium hydroxide solution and water, dried and evaporated to dryness.The product is recrystallised from cyclohexane/ethyl acetate. Yield: 47g 20 g (66.2 mmol)2,2,2-trifluoro-1-[4-(4-nitro-phenyl)-piperidin-1-yl]-ethanone and 32 g(23.2 mmol) potassium carbonate are placed in 400 ml of methanol andstirred for 48 hours at ambient temperature. Then the reaction mixtureis concentrated by evaporation, the residue is extracted with water anddichloromethane. The organic phase is dried and evaporated to dryness.The hydrochloride is precipitated. Yield: 15 g

6.0 g (24.7 mmol) 4-(4-nitro-phenyl)-piperidine-hydrochloride are placedin 300 ml of tetrahydrofuran and combined successively with 11 ml (61.8mmol) diisopropylethylamine, 5 ml (49.4 mmol) formaldehyde (37% inwater) and 13 g (61.8 mmol) sodium triacetoxyborohydride. The reactionmixture is stirred for 16 hours at ambient temperature, then poured ontowater and concentrated by evaporation. The aqueous residue is made basicwith 2 N sodium hydroxide solution and extracted with dichloromethane.The combined organic phases are dried and evaporated to dryness. Yield:4.5 g

4.3 g (19.5 mmol) 1-methyl-4-(4-nitro-phenyl)-piperidine are dissolvedin a mixture of 60 ml of ethanol and 60 ml THF, combined with 2 gpalladium/charcoal (10%) and hydrogenated at 1 bar hydrogen. Then thereaction mixture is suction filtered and the filtrate is concentrated byevaporation. Yield: 3.5 g

4-(1-CYCLOPROPYLMETHYL-PIPERIDIN-4-YL)-PHENYLAMINE

6.0 g (24.7 mmol) of the intermediate described above,4-(4-nitro-phenyl)-piperidine-hydrochloride, are placed in 300 ml oftetrahydrofuran and combined successively with 11 ml (61.8 mmol)diisopropylethylamine, 3.7 ml (49.4 mmol) cyclopropane carboxaldehydeand 13 g (61.8 mmol) sodium triacetoxyborohydride. The reaction mixtureis stirred for 3 hours at ambient temperature, then poured onto waterand concentrated by evaporation. The aqueous residue is extracted withdichloromethane, the organic phase is dried and evaporated to dryness.The aqueous phase is made basic with 2 N sodium hydroxide solution, thenextracted with dichloromethane. The organic phase is dried andevaporated to dryness. Yield: 5.6 g

3.3 g (12.5 mmol) 1-cyclopropylmethyl-4-(4-nitro-phenyl)-piperidine aredissolved in a mixture of 40 ml of ethanol and 40 ml THF, combined with1.3 g palladium/charcoal (10%) and hydrogenated at 1 bar hydrogen. Thenthe reaction mixture is suction filtered and the filtrate isconcentrated by evaporation. Yield: 2.7 g

1,1-DIMETHYL-2-DIMETHYLAMINO-1-YL-ETHYLAMINE AND1,1-DIMETHYL-2-PIPERIDIN-1-YL-ETHYLAMINE

The compounds were prepared according to the following references: a) S.Schuetz et al. Arzneimittel-Forschung 1971, 21, 739-763 b) V. M. Belikovet al. Tetrahedron 1970, 26, 1199-1216. c) E. B. Butler and McMillan J.Amer. Chem. Soc. 1950, 72, 2978.

Other amines were prepared as follows according to a modification of theliterature mentioned above.

1,1-DIMETHYL-2-MORPHOLIN-1-YL-ETHYLAMINE

8.7 ml morpholine and 9.3 ml 2-nitropropane are taken, while coolingwith ice, and 7.5 ml formaldehyde (37% in water) and 4 ml of a 0.5 mol/LNaOH solution are slowly added dropwise (<10° C.). Then the mixture isstirred for 1 h at 25° C. and for 1 h at 50° C. The solution is treatedwith water and ether and the aqueous phase is extracted 3× with ether.The combined organic phases are dried over sodium sulphate and combinedwith hydrochloric acid in dioxane (4 mol/L), the precipitate formed issuction filtered.

Yield: 21.7 g of colourless powder

5 g of the white powder are dissolved in 80 ml of methanol and with theaddition of 2 g RaNi treated with hydrogen at 35° C. and 50 psi for 40minutes. This yields 3.6 g of 1,1-dimethyl-2-morpholin-1-yl-ethylamine.

The following amine is prepared analogously to this method:

1,1-DIMETHYL-N-METHYLPIPERAZIN-1-YL-ETHYLAMINE

1,3-DIMORPHOLIN-2-AMINO-PROPANE

5 g 1,3-dimorpholine-2-nitropropane are dissolved in 80 ml of methanoland with the addition of 2 g RaNi treated with hydrogen at 30° C. and 50psi for 5.5 h. This yields 4.2 g 1,3-dimorpholin-2-amino-propane.

TRANS-N,N-DIBENZYL-CYCLOHEXANE-1,4-DIAMINE

33 g (112 mmol) 4-dibenzylaminocyclohexanone are dissolved in 300 ml ofmethanol, combined with 17.4 g (250 mmol) hydroxylamine hydrochlorideand stirred for 4 h at 60° C. The solvent is evaporated down in vacuo,combined with 500 ml of water and 50 g potassium carbonate and extractedtwice with 300 ml dichloromethane. The organic phase is dried,evaporated down in vacuo, the residue is crystallised from petroleumether, dissolved in 1.5 L ethanol and heated to 70° C. 166 g sodium areadded batchwise and the mixture is refluxed until the sodium dissolves.The solvent is eliminated in vacuo, the residue is combined with 100 mlof water and extracted twice with 400 ml ether. The org. phase is washedwith water, dried, evaporated down in vacuo and the trans-isomer isisolated through a column (approx. 1.5 L silica gel; approx. 2 L ethylacetate 80/methanol 20+2% conc. ammonia). Yield: 12.6 g

TRANS-N,N-DIMETHYL-CYCLOHEXANE-1,4-DIAMINE (DIMETHANESULPHONATE)

4 g (13.6 mmol) trans-N,N-dibenzyl-cyclohexane-1,4-diamine are placed in8.1 g (100 mmol) formalin solution (37% in water) and 20 ml (43.4 mmol)formic acid and refluxed for 2 hours. The reaction mixture is added toice water and combined with conc. ammonia. It is extracted with ethylacetate. The organic phase is washed with water, dried and evaporated todryness. The residue is crystallised from acetone and methanesulphonicacid. Yield: 6 g (M.p.: 203-204° C. 6 g (11.7 mmol)trans-N,N-dibenzyl-N′,N′-dimethyl-cyclohexane-1,4-diamine-dimethanesulphonateare placed in 120 ml of methanol, 1.2 g palladium/charcoal (10%) areadded and then the mixture is hydrogenated at 50 psi and 20° C. Thereaction mixture is suction filtered through kieselguhr, the motherliquor is concentrated by evaporation. The residue is crystallised fromacetone. Yield: 3.5 g

CIS- AND TRANS-4-MORPHOLINO-CYCLOHEXYLAMINE

3.9 g (30 mmol) 4-dibenzylaminocyclohexanone are dissolved in 100 mldichloromethane and stirred with 3.9 g (45 mmol) morpholine and 9.5 g(45 mmol) sodium triacetoxyborohydride for 12 h at RT. Then the mixtureis combined with water and potassium carbonate, the organic phase isseparated off, dried and the solvent is eliminated in vacuo. The residueis purified through a silica gel column (approx 20 ml silica gel; approx500 ml of ethyl acetate 90/methanol 10+1% conc. ammonia). The requiredfractions are evaporated down in vacuo.

Yield: 6.6 g cis-isomer and 2 g trans-isomer.

Alternatively the trans-dibenzyl-4-morpholino-cyclohexylamine may beprepared as follows:

6.8 g (23 mmol) trans-N,N-dibenzyl-cyclohexane-1,4-diamine are dissolvedin 90 ml DMF and stirred with 5 ml (42 mmol) 2,2′-dichloroethylether and5 g potassium carbonate for 8 h at 100° C. After cooling the mixture iscombined with 30 ml of water, precipitated crystals are suction filteredand purified through a short column (approx. 20 ml silica gel, approx.100 ml of ethyl acetate). The residue is crystallised from methanol andconc. HCl as the dihydrochloride. Yield: 7.3 g

7.2 g (16.4 mmol) trans-dibenzyl-4-morpholino-cyclohexylamine aredissolved in 100 ml of methanol and hydrogenated on 1.4 g Pd/C (10%) at30-50° C. The solvent is eliminated in vacuo and the residuecrystallised from ethanol and conc. HCl.

Yield: 3.9 g (M.p. 312° C.). The cis-isomer may be prepared analogously.

CIS- AND TRANS-4-PIPERIDINO-CYCLOHEXYLAMINE

2.0 g (6.8 mmol) trans-1-amino-4-dibenzylaminocyclohexane (see precedingExample) are dissolved in 50 ml DMF and stirred with 1.6 g (7 mmol)1,5-dibromopentane and 2 g potassium carbonate 48 h at RT. It is cooled,combined with water, extracted twice with 100 ml dichloromethane, driedand the solvent is eliminated in vacuo. The residue is purified througha column (approx. 100 ml silica gel, approx. 500 ml of ethyl acetate80/methanol 20+1% conc. ammonia). The required fractions are evaporateddown in vacuo and crystallised from petroleum ether. Yield: 1.2 g

1.7 g (4.8 mmol) trans-dibenzyl-4-piperidino-cyclohexylamine aredissolved in 35 ml of methanol and hydrogenated on 350 mg Pd/C (10%) at20° C. The solvent is eliminated in vacuo and the residue iscrystallised from ethanol and conc. HCl. Yield: 1.1 g. The cis-isomermay be prepared analogously.

CIS- AND TRANS-4-(4-PHENYL-PIPERAZIN-1-YL)-CYCLOHEXYLAMINE

4.1 g (25.3 mmol) 4-dibenzylaminocyclohexanone are dissolved in 50 mldichloromethane and stirred with 7.4 g (25.3 mmol) N-phenylpiperazineand 7.4 g (35 mmol) sodium triacetoxyborohydride for 12 h at RT. Thenthe mixture is combined with water and potassium carbonate, the organicphase is separated off, dried and the solvent is eliminated in vacuo.The residue is purified through a silica gel column (ethyl acetate80/methanol 20+0.5% conc. ammonia). Yield: 1.7 g cis-isomer and 0.27 gtrans-isomer.

270 mg (0.61 mmol)trans-dibenzyl-[4-(4-phenyl-piperazin-1-yl)-cyclohexyl]-amine aredissolved in 5 ml of methanol and hydrogenated on 40 mg Pd/C (10%) at20-30° C. The solvent is eliminated in vacuo and the residue iscrystallised from ethanol and conc. HCl. Yield: 110 mg. The cis-isomermay be prepared analogously.

CIS-4-(4-CYCLOPROPYLMETHYL-PIPERAZIN-1-YL)-CYCLOHEXYLAMINE

9.8 g (33.4 mmol) 4-dibenzylcyclohexanone are dissolved in 100 mldichloromethane and stirred with 5.6 g (40 mmol)N-cyclopropylmethylpiperazine and 8.5 g (40 mmol) sodiumtriacetoxyborohydride for 12 h at RT. Then the mixture is combined withwater and potassium carbonate, the organic phase is separated off, driedand the solvent is eliminated in vacuo. The residue is purified througha silica gel column (approx. 50 ml silica gel, approx. 3 L ethyl acetate95/methanol 5+0.25% conc. ammonia). The required fractions areevaporated down in vacuo.

Yield: 8.5 g cis-isomer and 2.2 trans-isomer.

8.5 g (20 mmol) cis-dibenzyl-[4-(4-cyclopropylmethyl-piperazin-1-yl)-cyclohexyl]-amine are dissolved in 170 ml ofmethanol and hydrogenated on 1.7 g Pd/C (10%) at 30-50° C. The solventis eliminated in vacuo and the residue is crystallised from ethanol andconc. HCl. Yield: 4.4 g

4-(4,4-DIMETHYL-PIPERIDIN-1YL)-CYCLOHEXYLAMINE

8.8 g (30 mmol) 4-dibenzylamino-cyclohexanone, 6.7 g (45 mmol)4,4-dimethyl-piperidine-hydrochloride and 9.5 g (45 mmol) sodiumtriacetoxyborohydride are stirred in 100 ml dichloromethane for 16 hoursat ambient temperature. 200 ml of water and 20 g potassium carbonate areadded, the organic phase is separated off and evaporated to dryness. Theresidue is purified by chromatography.

Yield: 0.7 g cis-isomer (M.p.: 125-126° C.) and 0.4 g trans-isomer. 0.7g (1.8 mmol)cis-dibenzyl-[4-(4,4-dimethyl-piperidin-1-yl)-cyclohexyl]-amine areplaced in 14 ml of methanol, 0.14 g palladium/charcoal (10%) are addedand the mixture is hydrogenated at 50 psi and 20° C. Then the catalystis suction filtered and the mother liquor is concentrated byevaporation. Yield: 0.3 g

CIS- AND TRANS-4-PYRROLIDIN-1-YL-CYCLOHEXYLAMINE (HYDROCHLORIDE)

0.8 g (21 mmol) lithium aluminium hydride are placed in 50 ml oftetrahydrofuran and 6.2 g (20 mmol) 4-dibenzylamino-cyclohexanone oxime(for preparation see above) dissolved in 62 ml of tetrahydrofuran areadded dropwise. Then the reaction mixture is refluxed for 3 hours withstirring. After cooling 0.8 ml of water and 2.4 ml 15% sodium hydroxidesolution are added dropwise. The precipitate formed is suction filteredand washed with tetrahydrofuran. The mother liquor is evaporated todryness.

Yield: 4.9 g (cis/trans-mixture)

2.9 g (10 mmol) cis/trans-N,N-dibenzyl-cyclohexane-1,4-diamine, 2.4 g(11 mmol)) 1,4-dibromobutane and 2.7 g potassium carbonate are placed in70 ml of dimethylformamide and stirred for 48 hours at ambienttemperature. Then the reaction mixture is concentrated by evaporation,the residue is extracted with water and dichloromethane. The organicphase is washed with water, dried and evaporated to dryness. The residueis purified by chromatography, corresponding fractions are combined,concentrated by evaporation and crystallised from petroleum ether.

Yield: 0.8 g cis-isomer (M.p.: 81-82° C.) and 0.9 g trans-isomer(122-124° C.). 2.2 g (6.1 mmol)trans-dibenzyl-(4-pyrrolidin-1-yl-cyclohexyl)-amine are placed in 40 mlof methanol and 0.4 g palladium/charcoal (10%) are added. The mixture ishydrogenated at 5 bar and 20° C. Then the catalyst is suction filtered,the mother liquor is combined with conc. hydrochloric acid andconcentrated by evaporation. The residue is stirred out with acetone.

Yield: 1.20 g. The cis isomer may be prepared analogously.

TRANS-4-(4-METHANESULPHONYL-PIPERAZIN-1-YL)-CYCLOHEXYLAMINE

14 g (47 mmol) 4-dibenzylamino-cyclohexanone, 8.5 g (51 mmol)1-methanesulphonyl-piperazine and 17.5 g (78 mmol) sodiumtriacetoxyborohydride are stirred in 250 ml dichloromethane for 4 hoursat ambient temperature. Then the reaction mixture is combined with 200ml of water and 20 g potassium carbonate. The organic phase is separatedoff, dried and evaporated to dryness. The residue is purified bychromatography. Yield: 4.8 g trans-isomer 4.8 g (11 mmol)trans-dibenzyl-[4-(4-methanesulphonyl-piperazin-1-yl)-cyclohexyl]-amineare dissolved in 100 ml of methanol and 2 g palladium/charcoal (10%) areadded. The mixture is hydrogenated at 50 psi and 50° C. Then thecatalyst is suction filtered, the mother liquor is concentrated byevaporation. The precipitate formed is suction filtered and washed withdiethyl ether. Yield: 2.4 g

CIS- ANDTRANS-4-(2,6-DIMETHYL-MORPHOLIN-4-YL)-CYCLOHEXYLAMINE-DIHYDROCHLORIDE

9 g (31 mmol) 4-dibenzylamino-cyclohexanone, 7.5 g (65 mmol)cis-2,6-dimethyl-morpholine and 9.5 g (45 mmol) sodiumtriacetoxyborohydride are stirred in 100 ml dichloromethane for 2 hoursat ambient temperature. Then 200 ml of water are added and the mixtureis made basic with potassium carbonate. The organic phase is separatedoff, dried and evaporated to dryness. The residue is purified bychromatography. Corresponding fractions are combined and concentrated byevaporation, then the hydrochloride is precipitated.

Yield: 10 g cis-isomer (M.p.: 304-305° C.) and 3.5 g trans-isomer(334-335° C.). 9.8 g (21 mmol)cis-dibenzyl-[4-(2,6-dimethyl-morpholin-4-yl)-cyclohexyl]-amine-dihydrochlorideare placed in 150 ml of methanol and 2 g palladium/charcoal (10%) areadded. The mixture is hydrogenated at 50 psi and 50° C. Then thecatalyst is suction filtered, the mother liquor is concentrated byevaporation. The precipitate formed is suction filtered and washed withdiethyl ether. Yield: 5.5 g. The trans isomer may be preparedanalogously.

CIS- AND TRANS-4-(4-METHYL-PIPERAZIN-1YL)-CYCLOHEXYLAMINE

14.7 g (50 mmol) 4-dibenzylamino-cyclohexanone, 15.8 g (100 mmol) ethylpiperazine-N-carboxylate and 10.6 g (50 mmol) sodiumtriacetoxyborohydride are stirred in 200 ml dichloromethane for 16 hoursat ambient temperature. Then the reaction mixture is combined with 200ml of water and 20 g potassium carbonate. The organic phase is separatedoff and evaporated to dryness. The residue is purified bychromatography. Yield: 12 g cis-isomer (M.p.: 143-144° C.) and 4 gtrans-isomer (281-282° C.).

12 g (27.5 mmol) ethylcis-4-(4-dibenzylamino-cyclohexyl)-piperazin-1-carboxylate are placed in50 ml of water and 50 ml of conc. hydrochloric acid, then refluxed for72 hours. Then the reaction mixture is concentrated by evaporation, theresidue is combined with 200 ml of water and 20 g potassium carbonateand extracted with dichloromethane. The organic phase is separated off,dried and evaporated to dryness. The residue is crystallised from ethylacetate. Yield: 8.6 g (M.p.: 100-101° C.)

4 g (11 mmol) cis-dibenzyl-(4-piperazin-1-yl-cyclohexyl)-amine areplaced in 5 ml (16.7 mmol) formalin solution (37% in water) and 10 ml(22 mmol) formic acid, then refluxed for 2 hours with stirring. Thereaction mixture is added to ice water and combined with conc. ammonia.It is extracted with diethyl ether. The organic phase is washed withwater, dried and evaporated to dryness. The residue is stirred out withpetroleum ether, suction filtered and dried. Yield: 4.10 g (M.p.: 93-94°C.)

4.1 g (11 mmol)cis-dibenzyl-[4-(4-methyl-piperazin-1-yl)-cyclohexyl]-amine are placedin 80 ml of methanol, 0.8 g palladium/charcoal (10%) are added and thenthe mixture is hydrogenated at 50 psi and 20° C. The reaction mixture issuction filtered through kieselguhr, the mother liquor is concentratedby evaporation. Yield: 1.90 g. The trans-isomer may be preparedanalogously.

SYNTHESIS OF THE INTERMEDIATE COMPOUNDS INTERMEDIATE COMPOUND 1.N-(7-OXO-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-2-YL)-ACETAMIDE

112 g (1.0 mol) 1,3-cyclohexanedione are suspended in 700 ml ice waterand 51.6 ml (1.0 mol) bromine are added dropwise at 0° C. within 45minutes. The suspension is stirred for 3.5 hours at max. 10° C. Then itis suction filtered and the solid is stirred out in 800 ml of water,suction filtered, washed with 3 L water and dried. The solid obtained isrecrystallised from ethanol. Yield: 37 g Z2a (m.p.: 159-160° C.)

15.5 g (0.2 mol) thiourea are placed in 200 ml of ethanol at ambienttemperature. 37.1 g (0.2 mol) Z2a are added batchwise to thissuspension, then it is rinsed with 60 ml of ethanol. The solutiongradually formed is refluxed for 2 hours with stirring and thenconcentrated by evaporation. The residue is extracted with water anddiethyl ether, the aqueous phase is made basic with sodium carbonatesolution. The resulting solid is suction filtered, washed with water,then stirred out with methanol and evaporated to dryness. Yield: 22 gZ3a (m.p.: 265-268° C.) ml (2.4 mol) acetic anhydride are taken atambient temperature, 22 g (0.13 mol) Z3a are added and the mixture isrefluxed for 3 hours with stirring. The suspension goes partially intosolution. After cooling with ice/saline bath the solid is suctionfiltered, decocted 2× in 150 ml acetone, suction filtered and dried.Yield: 25 g Z4a (m.p.: 268-272° C.)

INTERMEDIATE COMPOUND 2.N-(6-FORMYL-7-OXO-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-2-YL)-ACETAMIDE

20 g (0.37 mol) sodium methoxide are suspended in 50 ml ofdimethylformamide, a suspension of 21 g (0.1 mol) intermediate compound1 in 100 ml of dimethylformamide is added dropwise. The mixture isstirred for 15 minutes, then cooled to 0° C. A mixture of 29.9 ml (0.37mol) ethyl formate and 60 ml benzene is added dropwise and the reactionmixture is diluted with another 100 ml benzene. Gradually a precipitateis formed and stirring is continued at 0° C. for 3.5 hours. Thesuspension is hydrolysed with 370 ml 1 molar hydrochloric acid, thesolid thus precipitated is suction filtered. The two phases of themother liquor are separated, the aqueous phase is extracted withdichloromethane. The resulting organic phase is dried and evaporated todryness. The solid and the residue from the extraction arerecrystallised from acetonitrile.

Yield: 20 g Z5a

INTERMEDIATE COMPOUND 3.N-(6-DIMETHYLAMINOMETHYLENE-7-OXO-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-2-YL)-ACETAMIDE

30 g (0.13 mol) intermediate compound 2 are suspended in 750 mldichloromethane and while cooling with ice combined with 1 ml glacialacetic acid and 30 ml dimethylamine (33% solution in THF). The reactionmixture is stirred overnight at ambient temperature, evaporated down andthe solid remaining is extracted with cyclohexane. Yield: 33 g Z5b

INTERMEDIATE COMPOUND 4.N-[6-(FURAN-2-CARBONYL)-7-OXO-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-2-YL]-ACETAMIDE

Analogously to the preparation of intermediate compound 21.7 g productZ5c are obtained from 2 g (10 mmol) intermediate compound 1, 1.6 g (30mmol) sodium methoxide and 3.8 g (30 mmol) methyl 2-furanoate. (m.p.:255-256° C.)

INTERMEDIATE COMPOUND 5.N-(6-BENZOYL-7-OXO-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-2-YL)-ACETAMIDE

Analogously to the preparation of intermediate compound 23.6 g productZ5d are obtained from 10 g (50 mmol) intermediate compound 1, 7.8 g (140mmol) sodium methoxide and 17.9 ml (140 mmol) methyl benzoate.

INTERMEDIATE COMPOUND 6.N-[6-(FURAN-3-CARBONYL)-7-OXO-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-2-YL]-ACETAMIDE

Analogously to the preparation of intermediate compound 24.8 g productZ5e are obtained from 7.5 g (40 mmol) intermediate compound 1, 7.7 g(110 mmol) sodium methoxide and 15.1 ml (110 mmol) ethylfuran-3-carboxylate.

INTERMEDIATE COMPOUND 7. METHYL(2-ACETYLAMINO-7-OXO-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-6-YL)-OXO-ACETATE

Analogously to the preparation of intermediate compound 252 g productZ5f^(Me) are obtained from 40 g (190 mmol) intermediate compound 1, 38 g(0.7 mol) sodium methoxide and 84 g (0.7 mol) dimethyl oxalate.

INTERMEDIATE COMPOUND 8. ETHYL(2-ACETYLAMINO-7-OXO-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-6-YL)-OXO-ACETATE

Analogously to the preparation of intermediate compound 278 g productZ₅f^(Et) are obtained from 73 g (348 mmol) intermediate compound 1, 54 g(1 mol) sodium methoxide and 152 g (1 mol) diethyl oxalate.

INTERMEDIATE COMPOUND 9.N-[7-OXO-6-(PYRIDINE-3-CARBONYL)-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-2-YL]-ACETAMIDE

Analogously to the preparation of intermediate compound 23.1 g productZ5g are obtained from 4 g (19 mmol) intermediate compound 1, 3.9 g (57mmol) sodium ethoxide and 7.9 g (57 mmol) methyl nicotinate.

INTERMEDIATE COMPOUND 10.N-(6-ACETYL-7-OXO-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-2-YL)-ACETAMIDE

1 g (4.8 mmol) intermediate compound 1 are dissolved in 20 ml THF,cooled to −20° C. and combined with 12 ml (12 mmol) of a 1 N solution oflithium hexamethyl disilazide in hexane. After 45 minutes at −20° C. 0.8g (7.2 mmol) 1-imidazol-1-yl-ethanone are added and the reaction mixtureis slowly heated to ambient temperature. After one hour at thistemperature the pH is adjusted to 6 with 2 N hydrochloric acid and themixture is extracted with ethyl acetate. The combined organic phases aredried and evaporated down. Yield: 1.2 g Z5h

INTERMEDIATE COMPOUND 11.N-[6-(1-METHYL-1H-IMIDAZOL-4-CARBONYL)-7-OXO-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-2-YL]-ACETAMIDE

Analogously to the preparation of intermediate compound 10 57 g productZ5i are obtained from 50 g (0.24 mol) intermediate compound 1, 714 ml(0.71 mol) LiHMDS (1 M in THF) and 55 g (0.31 mol)imidazol-1-yl-(1-methyl-1H-imidazol-4-yl)-methanone.

INTERMEDIATE COMPOUND 12.N-(6-ISOBUTYRYL-7-OXO-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-2-YL)-ACETAMIDE

Analogously to the preparation of intermediate compound 104.4 g productZ5j are obtained from 4.8 g (23 mmol) intermediate compound 1, 71 ml (71mmol) LiHMDS (1 M in hexane) and 6.3 g (46 mmol)1-imidazol-1-yl-2-methyl-propan-1-one.

INTERMEDIATE COMPOUND 13.N-[6-(2-METHOXY-ACETYL)-7-OXO-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-2-YL]-ACETAMIDE

Analogously to the preparation of intermediate compound 101.8 g productZ5k are obtained from 4.2 g (20 mmol) intermediate compound 1, 60 ml (60mmol) LiHMDS (1 M in hexane) and 5.6 g (40 mmol)1-imidazol-1-yl-2-methoxy-ethanone.

INTERMEDIATE COMPOUND 14.(R)—N-[7-OXO-6-(TETRAHYDRO-FURAN-2-CARBONYL)-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-2-YL]-ACETAMIDE

Analogously to the preparation of intermediate compound 10 1 g productZ5l are obtained from 10 g (48 mmol) intermediate compound 1,145 ml (145mmol) LiHMDS (1 M in hexane) and 23.5 g (52 mmol)(R)-imidazol-1-yl-(tetrahydro-furan-2-yl)-methanone.

INTERMEDIATE COMPOUND 15.(S)—N-[7-OXO-6-(TETRAHYDRO-FURAN-2-CARBONYL)-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-2-YL]-ACETAMIDE

Analogously to the preparation of intermediate compound 103.1 g productZ5m are obtained from 19.4 g (92 mmol) intermediate compound 1, 277 ml(277 mmol) LiHMDS (1 M in hexane) and 23.5 g (141 mmol)(S)-imidazol-1-yl-(tetrahydro-furan-2-yl)-methanone.

INTERMEDIATE COMPOUND 16.N-[7-Oxo-6-(3-TRIMETHYLSILANYL-PROPYNOYL)-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-2-YL]-ACETAMIDE

Analogously to the preparation of intermediate compound 101.1 g productZ5n are obtained from 1.1 g (5.7 mmol) intermediate compound 1, 17.5 ml(17.5 mmol) LiHMDS (1 M in hexane) and 4.6 g (8.4 mmol)1-imidazol-1-yl-3-trimethylsilanyl-propynone.

INTERMEDIATE COMPOUND 17.N-{7-OXO-6-[1-(2-TRIMETHYLSILANYL-ETHOXYMETHYL)-1HIMIDAZOL-4-CARBONYL]-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-2-YL}-ACETAMIDE

A solution of 125 ml (0.125 mol) LHMDS (lithium hexamethyl disilazide)in 100 mL tetrahydrofuran is combined with 10.5 g (50 mmol) intermediatecompound 1 at −20° C. and stirred for 0.75 hours. 15.6 g (53 mmol)imidazol-1-yl-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-methanonedissolved in 80 ml of tetrahydrofuran are added. The resultingsuspension is stirred for 16 hours at ambient temperature. Then it ishydrolysed with 2 N hydrochloric acid and extracted withmethyl-tert-butylether. The organic phase is dried and evaporated todryness. The residue is purified by chromatography. Yield: 1.5 g

INTERMEDIATE COMPOUND 18. ETHYL2-ACETYLAMINO-7-OXO-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-6-CARBOXYLATE

4.0 g (19 mmol) intermediate compound 1 are placed in 120 ml oftetrahydrofuran and cooled to −50° C. 80 ml (60 mmol) of a 1 molarsolution of lithium bis(trimethylsilylamide) in tetrahydrofuran areadded and the mixture is stirred for 5 hours at −30° C. to −50° C. Thenthe reaction mixture is combined with 6.5 ml (80 mmol) chloroethylformate, then stirred for 1 hour. 50 ml of water are added, the mixtureis acidified with 2 N hydrochloric acid and extracted with ethylacetate. The organic phase is dried and evaporated to dryness. Theresidue is purified by chromatography, corresponding fractions arecombined and concentrated by evaporation. The crude product istriturated with diethyl ether and suction filtered. Yield: 2.3 g Z5o

INTERMEDIATE COMPOUND 19.N-[7-OXO-6-(2,2,2-TRIFLUORO-ACETYL)-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-2-YL]-ACETAMIDE

140 g (1.25 mol) 1,3-cyclohexanedione are dissolved in 625 mlchloroform, then 145 ml (2.49 mol) ethanol and 3.4 g (18 mmol)p-toluenesulphonic acid are added. The reaction mixture is refluxed for72 hours with stirring, while the resulting water is separated off usingthe water separator. Then the mixture is concentrated by evaporation andthe residue is combined with diethyl ether, dried and evaporated todryness. The residue is purified by distillation. Yield: 166 g

4.6 g (0.115 mol) sodium hydride are suspended in 250 ml diethyl etherand heated to 40° C. Then a solution of 17 ml (0.14 mol) ethyltrifluoroacetate and 10 g (71 mmol) of the intermediate described abovein 50 ml diethyl ether is added dropwise. The mixture is refluxed for 24hours with stirring. After cooling to ambient temperature 150 ml ofwater are added and the mixture is stirred for 0.1 hour at ambienttemperature. The phases are separated, the organic phase is extractedwith 5% sodium hydroxide solution. The combined basic aqueous phases areacidified and extracted with ethyl acetate. The ethyl acetate phases aredried and evaporated to dryness. The crude product is purified bychromatography. Yield: 4.1 g

0.4 g (1.7 mmol) of the intermediate described above are dissolved in 10ml dioxane and 10 ml of water, cooled to −10° C. and then combined with0.3 g (1.9 mmol) N-bromosuccinimide. The mixture is stirred for 1 hourat ambient temperature and then 0.13 g (1.7 mmol) thiourea are added.The mixture is stirred for 0.5 hours at ambient temperature and for 3hours at 80° C. After cooling the reaction mixture is made basic andextracted with dichloromethane. The organic phase is dried andevaporated to dryness. Yield: 0.2 g

0.2 g (0.76 mmol) of the intermediate described above are suspended in10 ml (0.1 mol) acetic anhydride and then heated to 100° C. The mixtureis stirred for 3 hours at 100° C. and for 16 hours at ambienttemperature. Then the reaction mixture is concentrated by evaporation,the residue is combined with glacial acetic acid and concentrated byevaporation. Yield: 0.3 g Z5p

INTERMEDIATE COMPOUND 20.1-PHENYL-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YLAMINE

650 ml 37% hydrochloric acid are placed in 650 ml of water and 99 g(0.27 mol)N-(1-phenyl-4,5-dihydro-1H-pyrazolo[3′,4′:3,4]benzo[1,2-d]thiazol-7-yl)-acetamide(prepared analogously to Example 1) are dissolved therein. The solutionis refluxed for 2 hours with stirring. After cooling to ambienttemperature the mixture is carefully made basic (pH 10-11) with sodiumhydroxide solution. The precipitate formed is suction filtered andstirred out with methanol. Yield: 66 g (m.p.: 307-308° C.)

INTERMEDIATE COMPOUND 21.N-(6-BROMO-7-OXO-4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-2-YL)-ACETAMIDE

A solution of 2 g (9.5 mmol) intermediate compound 1 in 60 ml glacialacetic acid is combined at ambient temperature with a solution of 1.5 g(9.5 mmol) bromine in 10 ml glacial acetic acid. The reaction mixture isslowly heated to 75° C., during which time rapid decolorisation sets in.It is evaporated to dryness, the residue is dissolved in methanol andthe product is precipitated by the addition of water. Yield: 2.2 g(M.p.: 180-182° C.)

INTERMEDIATE COMPOUND 22.N-(5-FORMYL-6-OXO-4,5,6,6A-TETRAHYDRO-3AH-CYCLOPENTATHIAZOL-2-YL)-ACETAMIDE

100 g (0.36 mol) 2-bromo-cyclopentane-1,3-dione (see M. Vanderwalle etal., Bull. Soc. Chim. Belg. 1966, 75, 648-654) are dissolved in 370 mlof dimethylformamide and combined with 43 g (0.36 mol) N-acetylthiourea.The mixture is stirred for 3 hours at 75° C., then at 50° C. 15 gactivated charcoal are added. After filtration through kieselguhr thefiltrate is cooled to 10° C. and combined with 1200 ml of water. Theprecipitate formed is stirred for 16 hours at ambient temperature,suction filtered and dried.

Yield: 20.4 g Z4b (m.p.: 270-272° C.) 27.6 g (0.51 mol) sodium methoxideare suspended in 50 ml of dimethylformamide and at ambient temperature asuspension of 20.0 g (0.10 mol) Z4b in 350 ml of dimethylformamide isadded dropwise in batches within 0.25 hours. The reaction mixture isstirred for 1 hour at ambient temperature, then heated to an internaltemperature of 60° C. A solution of 41 ml (0.51 mol) ethyl formate in 40ml benzene is added dropwise and the mixture is stirred for 2 hours.After cooling to 5° C. 100 ml semiconcentrated hydrochloric acid areadded and the mixture is diluted with water to 3000 ml. A precipitate isformed which is suction filtered. The filtrate is extracted withdichloromethane, the organic phase is dried and evaporated to dryness.The residue is stirred with dichloromethane/diethyl ether 1:5, suctionfiltered and dried.

Yield: 12.3 g Z5q

INTERMEDIATE COMPOUND 23.N-(7-FORMYL-8-OXO-5,6,7,8-TETRAHYDRO-4H-CYCLOHEPTATHIAZOL-2-YL)-ACETAMIDE

A solution of 7.4 g (90 mmol) sodium acetate and 9.9 g (79 mmol)1,3-cycloheptadiene in 300 ml glacial acetic acid is combined at 15° C.with 12.6 g (79 mmol) bromine and stirred for 30 min. Then 6.0 g (79mmol) thiourea are added and the suspension is refluxed for 5 hours. Theacetic acid is eliminated in vacuo and the residue is taken up insaturated saline solution. Insoluble constituents are suction filteredand the aqueous phase is first of all extracted with ether and then madealkaline with ammonia. The precipitated solid is suction filtered anddried. Yield: 3.7 g Z3b

3.7 g (20 mmol) of compound Z3b are refluxed in 50 ml acetic anhydridefor 1 hour. The solid precipitated after cooling is suction filtered andstirred with ether. Yield: 2.4 g Z4c

1.7 g (31 mmol) sodium methoxide are suspended in 20 ml DMF and combinedbatchwise with 2.4 g (11 mmol) of compound Z4c. After 30 min the mixtureis cooled to −5° C., a solution of 2.5 ml (31 mmol) ethyl formate in 10ml benzene is added dropwise and the resulting mixture is stirredovernight at ambient temperature. It is combined with 70 ml 1Nhydrochloric acid, the precipitate formed is suction filtered and washedwith water. Yield: 2 g Z5r

SYNTHESIS OF COMPOUNDS OF FORMULA 1 EXAMPLE 1N-(1-P-TOLYL-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL)-ACETAMIDE

0.5 g (2 mmol) intermediate compound 2 are placed in 7.5 ml glacialacetic acid, combined with 0.32 g (2 mmol)p-tolylhydrazine-hydrochloride and heated to 60° C. for 3.5 hours. Theprecipitate formed after the addition of 20 ml of water is suctionfiltered and recrystallised from acetonitrile with the addition ofactivated charcoal. Yield: 0.32 g (m.p.: 240-242° C.)

EXAMPLE 2N-[1-(5-FLUORO-2-METHYL-PHENYL)-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL]-ACETAMIDE

8.8 mg (0.05 mmol) 5-Fluoro-2-methyl-phenylhydrazine-hydrochloride areplaced in 2.5 ml of ethanol and combined with 13.3 mg (0.05 mmol)intermediate compound 3, dissolved in 2.5 ml of ethanol. The reactionmixture is heated overnight to 50° C., evaporated down and the residueis purified by RP-HPLC. Yield: 13.3 mg

EXAMPLE 37-ACETYLAMINO-4,5-DIHYDRO-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOLE-1-CARBOXYLICACID AMIDE

14 g (59 mmol) intermediate compound 2 and 6.7 g (60 mmol) semicarbazideare suspended in 130 ml of water and refluxed for 1 hour. The solid issuction filtered and purified by chromatography. Yield: 5.6 g (M.p.:265-270° C.)

EXAMPLE 41-(4-NITRO-PHENYL)-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YLAMINE

Analogously to Example 1 14 g product are obtained from 15 g (63 mmol)intermediate compound 2 and 9.8 g (64 mmol) 4-nitrophenylhydrazine(M.p.: 300-310° C.).

7 g (20 mmol) of this intermediate are saponified with 90 mlsemiconcentrated hydrochloric acid as described for intermediate 20.

5.2 g product are obtained (M.p.: 273-278° C.).

EXAMPLE 5 N-(1-PHENYL-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL)-FORMAMIDE

A mixture of 0.25 g (0.9 mmol) intermediate compound 20 in 8 ml phenylformate is stirred for 4 hours at 60° C. After cooling to ambienttemperature the precipitate is suction filtered and washed with a littleacetone. The crude product is recrystallised from acetonitrile with theaddition of activated charcoal. Yield: 0.11 g (m.p.: 273-277° C.)

EXAMPLE 6 METHYL(1-PHENYL-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL)-CARBAMOYLATE

0.50 g (1.9 mmol) intermediate compound 20 are suspended in 10 ml ofpyridine and heated to 50° C. 0.6 ml (7.6 mmol) chloroethyl formate areslowly added and the reaction mixture is then stirred for 48 hours at50° C. During this time a further 2×0.6 ml of chloroethyl formate areadded. The mixture is stirred for another 72 hours at ambienttemperature. The suspension is filtered, the filtrate is combined with130 ml of water. The precipitate formed is suction filtered, washed anddried. The crude product is recrystallised from methanol. Yield: 0.15 g(m.p.: 283-287° C.)

EXAMPLE 74-DIMETHYLAMINO-N-(1-PHENYL-4,5-DIHYDRO-1H-PYRAZOLO-[3′,4′:3,4]BENZO[1,2-D]THIAZOL-7-YL)-BUTYRAMIDE

In a sealable pressure tube 0.9 g (4.8 mmol) freshly prepared4-(dimethylamino)-butyric acid chloride-hydrochloride are suspended in30 ml of tetrahydrofuran and heated to 50° C. 0.6 ml triethylamine areadded, followed by 0.5 g (1.9 mmol) intermediate compound 20 addedbatchwise. The reaction mixture is stirred for 71 hours at 70° C. Aftercooling to ambient temperature the precipitate formed is suctionfiltered, washed and taken up in saturated sodium hydrogen carbonatesolution and chloroform. The organic phase is washed with water, driedand evaporated to dryness. The crude product is recrystallised fromacetonitrile with the addition of activated charcoal. Yield: 0.2 g(m.p.: 165-166° C.)

EXAMPLE 8 S-ETHYL(1-PHENYL-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL)-THIOCARBAMOYLATE

2.7 g (9.9 mmol) intermediate compound 20 are placed in 70 ml ofpyridine and heated to 50° C. 1.6 ml (15 mmol) ethyl thiochloroformateare added to this suspension. The resulting solution is stirred for 2hours at 50° C. After cooling to ambient temperature the solution isadded to 700 ml of water, the precipitate formed is suction filtered,washed and dried. Yield: 2.2 g

EXAMPLE 9(1-PHENYL-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL)-UREA

In a sealable pressure tube 7 ml (14 mmol) 2 molar ethanolic ammoniasolution are added to a suspension of 0.5 g (1.4 mmol) of the compounddescribed in Example 8 in 9 ml of ethanol. The tube is sealed and thereaction mixture is stirred for a total of 24 hours at 80° C. After 5hours reaction a further 3 ml (6 mmol) of the ammonia solution areadded. After cooling to ambient temperature the precipitate formed issuction filtered, washed and dried. The crude product is recrystallisedfrom isopropanol with the addition of activated charcoal. Yield: 0.16 g(m.p.: 321-325° C.)

EXAMPLE 103-METHANESULPHONYL-PHENYL-(1-PHENYL-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL)-AMINE

A mixture of 0.5 g (2 mmol) intermediate compound 20, 0.5 g (2 mmol)1-bromo-3-methanesulphonylbenzene, 0.13 g (0.4 mmol)tri-tert-butylphosphine tetrafluoroborate, 0.2 g (0.2 mmol)tris(dibenzylideneacetone)-dipalladium (0) and 0.2 g (2 mmol) sodiumcarbonate in 10 ml DMF is stirred for 48 hours at 90° C. The reactionmixture is combined with dichloromethane and water and the aqueous phaseis extracted with dichloromethane. The combined organic phases aredried, evaporated down and the residue remaining is purified by columnchromatography. Yield: 25 mg

EXAMPLE 111-TERT-BUTYL-3-{4-[3-(1-PHENYL-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL)-UREIDO]-BUT-2-YNYL}-UREA

A solution of 0.4 g (1.5 mmol) intermediate compound 20 in 0.5 ml ofpyridine, 3 ml dichloromethane and 0.5 ml THF is combined with 0.4 g (2mmol) 4-nitrophenyl chloroformate and stirred for 2 hours at ambienttemperature. Then the reaction mixture is combined with 0.5 g (2.7 mmol)tert-butyl (4-amino-but-2-ynyl)-carbamoylate and 1 ml of pyridine andstirred for a further 24 hours. After the addition of dichloromethaneand water the aqueous phase is extracted with dichloromethane. Thecombined organic phases are evaporated down and the residue remaining ispurified by column chromatography. Yield: 0.2 g (M.p.: 196° C.)

EXAMPLE 121-(4-AMINO-BUT-2-YNYL)-3-(1-PHENYL-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL)-UREA

0.1 g (0.2 mmol) of the compound obtained in Example 11 are suspended in0.5 ml trifluoroacetic acid and 2 ml dichloromethane and stirredovernight at ambient temperature. The reaction mixture is evaporateddown, the residue taken up in acetone and the product is precipitated bythe addition of ethereal hydrochloric acid.

Yield: 0.1 g (M.p.: 232° C.)

EXAMPLE 132-[(1-ETHYL-PYRROLIDIN-2-YLMETHYL)-AMINO]-N-(1-PHENYL-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL)-ACETAMIDE

0.8 g (6.2 mmol) bromoacetic acid are dissolved in 20 ml DMF, combinedwith 4.9 g N-cyclohexylcarbodiimide-N′-methyl-polystyrene HL (1.9mmol/g) and stirred for 30 minutes at ambient temperature. Then asolution of 0.83 g (3.1 mmol) intermediate compound 20 is added and themixture is stirred overnight. The polymer is suction filtered and washedwith DMF. The filtrate is evaporated down and the residue is trituratedin ethyl acetate/diisopropylether. Yield: 1 g

6 mg (0.048 mmol) C-(1-ethyl-pyrrolidin-2-yl)-methylamine are dissolvedin 0.4 ml DMF and combined with 0.02 ml (0.12 mmol) triethylamine,dissolved in 0.1 ml DMF. Then 16 mg (0.04 mmol) of a solution of thebromide intermediate described above in 0.5 ml DMF are added. Thereaction mixture is stirred overnight and then evaporated down. Yield: 4mg.

EXAMPLE 142-AMINO-N-(1-PHENYL-4,5-DIHYDRO-1H-PYRAZOLO-[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL)-ACETAMIDE

26 mg of the bromide intermediate obtained in the first part of Example13 are suspended in 3 ml 33% aqueous ammonia solution and stirredovernight at ambient temperature. The reaction mixture is extracted withdichloromethane and the combined organic phases are evaporated down. Theresidue is purified by RP-HPLC. Yield: 8 mg

EXAMPLE 152-HYDROXY-N-(1-PHENYL-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL)-ACETAMIDE

26 mg of the bromide intermediate obtained in the first part of Example13 are suspended in 2 ml of water and 1 ml DMF and stirred for 48 hoursat 100° C. The reaction mixture is purified by RP-HPLC. Yield: 9 mg

EXAMPLE 16N-{1-[4-(MORPHOLIN-4-CARBONYL)-PHENYL]-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL}-ACETAMIDE

A solution of 3.5 mg (0.01 mmol)4-(7-acetylamino-4,5-dihydro-pyrazolo[3′,4′:3,4]benzo[1,2-d]thiazol-1-yl)-benzoicacid (prepared analogously to Example 1) in 0.5 ml DMF is combined with4 μL (0.03 mmol) triethylamine and 4 mg (0.01 mmol)O-pentafluorophenyl-1,1,3,3-tetramethyluronium hexafluorophosphate(PFTU) and stirred for 15 minutes. A solution of 1 mg (0.01 mmol)morpholine in 0.5 ml DMF is added to this mixture and it is shaken for12 hours at ambient temperature. Then 3 mg polyamine resin HL (0.01mmol, 200-400 mesh) are added and the mixture is shaken for a further 8hours. The resin is filtered off and the filtrate is evaporated todryness in vacuo.

EXAMPLE 17N-{1-[4-(4-AMINO-PIPERIDINE-1-CARBONYL)-PHENYL]-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL}-ACETAMIDE

A solution of 0.3 g (0.85 mmol))4-(7-acetylamino-4,5-dihydro-pyrazolo[3′,4′:3,4]benzo[1,2-d]thiazol-1-yl)-benzoicacid (prepared analogously to Example 1), 0.32 g (1.00 mmol) TBTU and0.75 ml (4.38 mmol) diisopropylethylamine in 25 ml dichloromethane isstirred for 15 minutes at ambient temperature and then combined with0.17 g (0.86 mmol) 4-N-Boc-aminopiperidine. After 2.5 hours the reactionmixture is poured onto 25 ml 5% potassium carbonate solution. Theorganic phase is dried and evaporated down. The residue is trituratedwith ethyl acetate/ether.

Yield: 0.43 mg (M.p.: 230° C.)

0.40 g (0.75 mmol) of the compound described previously are suspended in10 ml ethereal hydrochloric acid and stirred for 72 hours at ambienttemperature. The solid is suction filtered and washed with ether. Yield:0.35 mg (M.p.: 269-270° C.)

EXAMPLE 18N-{1-[4-(7-ACETYLAMINO-4,5-DIHYDRO-PYRAZOLO[3′,4′:3,4]-BENZO[1,2-d]THIAZOL-1-YL)-BENZOYL]-PIPERIDIN-4-YL}-2-PHENYL-ACETAMIDE

A solution of 12 mg (0.09 mmol) phenylacetic acid, 33 mg (0.09 mmol)TBTU and 80 μL (0.47 mmol) diisopropylethylamine in 2 ml dichloromethaneis stirred for 15 minutes at ambient temperature and then combined with40 mg (0.09 mmol) of the compound described in Example 17. After 2.5hours the reaction mixture is poured onto 5% potassium carbonatesolution. The organic phase is dried and evaporated down. The residue istriturated with ethyl acetate. Yield: 34 mg (M.p.: 271-272° C.)

EXAMPLE 19N-[1-(4-METHYLSULPHAMOYL-PHENYL)-4,5-DIHYDRO-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL]-ACETAMIDE

3.0 g (7.7 mmol)4-(7-acetylamino-4,5-dihydro-pyrazolo[3′,4′:3,4]benzo[1,2-d]thiazol-1-yl)-benzenesulphonicacid (prepared analogously to Example 1) are placed in 180 ml phosphorusoxychloride, and 1.6 g (7.7 mmol) phosphorus pentachloride are addedwith cooling. The suspension is stirred for 3 hours at 90° C. and for 16hours at ambient temperature, then cooled to 5° C. Within 0.75 hours thereaction solution is added dropwise to ice, then extracted withchloroform. The organic phase is dried and evaporated to dryness. Yield:1.3 g

0.15 g (0.37 mmol) of the sulphonic acid chloride described previouslyand 2 ml (4.0 mmol) methylamine (2 M in THF) are placed In a pressurisedreaction vessel, then the mixture is stirred for 1 hour at ambienttemperature. The solution is concentrated by evaporation, the residue iscrystallised from ethanol. The crude product is recrystallised frommethanol. Yield: 0.02 g (m.p.: >260° C.)

EXAMPLE 20N-(1-CYCLOHEX-2-ENYL-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL)-ACETAMIDEEXAMPLE 21N-(2-CYCLOHEX-2-ENYL-4,5-DIHYDRO-2H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL)-ACETAMIDE

4.0 g (16.8 mmol) intermediate compound 2 are suspended in 50 ml glacialacetic acid and combined with 1.6 g (16.8 mol) hydrazine-acetate. Themixture is stirred for 3.5 hours at 60° C. stirred and then 150 ml ofwater are added. The precipitate formed is suction filtered, washed anddried. Yield: 2.8 g (m.p.: 261-264° C.)

0.2 g (0.85 mmol) of the intermediate described above are dissolved in 2ml dimethylacetamide and combined with 0.1 g (2.5 mmol) sodium hydroxide(ground). It is stirred for 0.5 hours at ambient temperature. Then 12 mg(0.035 mmol) tetrabutylammonium hydrogen sulphate and 0.09 ml (0.9 mmol)3-bromocyclohexene are added. The reaction mixture is stirred for 3hours at 120° C. It is concentrated by evaporation, the residue isextracted with water and dichloromethane. The combined organic phasesare dried and evaporated to dryness. The crude product is purified bychromatography.

Yield: 0.020 g (m.p.: 247-249° C., Example 21);

Yield: 0.060 g (m.p.: 213-214° C., Example 20)

EXAMPLE 22N-(1-BENZOYL-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL)-ACETAMIDEEXAMPLE 23N-(2-BENZOYL-4,5-DIHYDRO-2H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL)-ACETAMIDE

0.2 g (0.85 mmol) of the intermediate described in Example 20/21 aresuspended in 2 ml benzene and combined with 0.25 ml (1.80 mmol)triethylamine and 0.18 ml (1.55 mmol) benzoyl chloride. The reactionmixture is stirred for 2 hours at 75° C. Then the suspension is suctionfiltered, the precipitate is washed with ethyl acetate and water. Yield:0.12 g (m.p.: 266-267° C., Example 23)

The mother liquor is concentrated by evaporation and the residue ispurified by chromatography.

Yield: 7 mg (Example 22)

EXAMPLE 24N-[1-(2-CHLORO-PHENYL)-3-FURAN-2-YL-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL]-ACETAMIDEEXAMPLE 25N-[2-(2-CHLORO-PHENYL)-3-FURAN-2-YL-4,5-DIHYDRO-2H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL]-ACETAMIDE

220 mg (0.7 mmol) intermediate compound 4 are placed in 3 ml glacialacetic acid and combined with 179 mg (0.7 mmol)2-chloro-phenylhydrazine-hydrochloride. The suspension is heatedovernight to 50° C., then combined with 20 ml of water and theprecipitate formed is suction filtered. The solid is purified by columnchromatography (eluant:dichloromethane/methanol 98:2).

Yield: 120 mg (yellow solid, m.p.: 265-266° C., Example 24); 38 mg(m.p.: >300° C., Example 25)

EXAMPLE 264-(7-ACETYLAMINO-3-FURAN-2-YL-4,5-DIHYDRO-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-1-YL)-3-CHLORO-N-(1-METHYL-PIPERIDIN-4-YL)-BENZAMIDE

Analogously to Example 1 a mixture of the two possible pyrazole isomersis obtained from 3.3 g (11 mmol) intermediate compound 4 and 2.1 g (11mmol) methyl 3-chloro-4-hydrazino-benzoate, and these are separated bycolumn chromatography.

Yield: 0.6 g isomer A; 0.7 g isomer B

0.7 g (1.5 mmol) of the isomer B described above are dissolved in 8 mldioxane and combined with a solution of 0.1 g (4.4 mmol) lithiumhydroxide in 1 ml of water. After 1.5 hours the reaction mixture isacidified with 2 N hydrochloric acid and the precipitated solid issuction filtered. The product is stirred with ether. Yield: 0.5 g

40 mg (0.09 mmol) of the acid described previously, 33 mg (0.09 mmol)HATU and 46 μL diisopropylethylamine are dissolved in 3 ml DMF andstirred for 10 minutes. Then a solution of 10 mg (0.09 mmol)methylaminopiperidine in 2 ml DMF is added and the mixture is stirredfor 2 hours. The reaction mixture is diluted with 15 ml 5% potassiumhydrogen carbonate solution and extracted with dichloromethane. Thecombined organic phases are washed with water, dried and evaporateddown. The crude product is purified by column chromatography. Yield: 24mg

EXAMPLE 27N-[1-(2-CHLORO-PHENYL)-3-FURAN-3-YL-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL]-ACETAMIDEEXAMPLE 28N-[2-(2-CHLORO-PHENYL)-3-FURAN-3-YL-4,5-DIHYDRO-2H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL]-ACETAMIDE

Analogously to Example 1, 102 mg (M.p. 265-266° C., Example 27); 12 mg(m.p.: >300° C., Example 28) are obtained from 0.5 g (1.2 mmol)intermediate compound 6 and 0.2 g (1.2 mmol)2-chloro-phenylhydrazine-hydrochloride after purification by columnchromatography.

EXAMPLE 29N-[1-(2-CHLORO-PHENYL)-3-ISOPROPYL-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL]-ACETAMIDE

Analogously to Example 1, 0.22 g product are obtained from 0.2 g (0.7mmol) intermediate compound 13 and 0.13 g (0.7 mmol)2-chloro-phenylhydrazine hydrochloride.

EXAMPLE 304-(7-ACETYLAMINO-3-METHOXYMETHYL-4,5-DIHYDRO-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-1-YL)-3-CHLORO-N-(1-METHYL-PIPERIDIN-4-YL)-BENZAMIDE

Analogously to Example 1, 1.2 g of product, whose ester function issaponified with 0.2 g (8.4 mmol) lithium hydroxide analogously toExample 26, is obtained from 0.9 g (3.2 mmol) intermediate compound 13and 0.7 g (3.2 mmol) methyl 3-chloro-4-hydrazino-benzoate. Then 50 mg ofthe acid obtained are subjected to amide coupling withmethylaminopiperidine as described in Example 26.

EXAMPLE 31 METHYL7-ACETYLAMINO-1-(2-CHLORO-PHENYL)-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOLE-3-CARBOXYLATE

Analogously to Example 1, 0.8 g product (M.p.: 294-297° C.) are obtainedfrom 1.0 g (3.4 mmol) intermediate compound 7 and 0.6 g (3.4 mmol)2-chloro-phenylhydrazine hydrochloride.

EXAMPLE 327-ACETYLAMINO-1-(2-CHLORO-PHENYL)-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOLE-3-CARBOXYLICACID

24 g (1 mol) of the compound described in Example 31 are placed in 250ml dioxane and a solution of 4 g (10 mmol) lithium hydroxide in 35 ml ofwater is added. The mixture is stirred for 16 hours at ambienttemperature. Then the solution is acidified slightly and the dioxane isconcentrated by evaporation. The suspension is diluted with water, thensuction filtered. The precipitate is dried. Yield: 23 g

EXAMPLE 337-ACETYLAMINO-1-PHENYL-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOLE-3-CARBOXYLICACID

Analogously to Example 1, 27 g product (M.p.: 298-300° C.) are obtainedfrom 30 g (0.1 mol) intermediate compound 7 and 10.3 ml (0.1 mol)phenylhydrazine. Of this, 0.1 g (0.3 mmol) are suspended in 12 ml ofmethanol/water (1:1) and combined with 0.4 ml 10% potassium hydroxidesolution. After 1.5 hours the reaction mixture is evaporated down andthe solution is acidified with dilute hydrochloric acid. The precipitateformed is recrystallised from acetonitrile. Yield: 0.1 g (M.p.: >300°C.)

EXAMPLE 34N-[3-AMINO-1-(2-CHLOROPHENYL)-4,5-DIHYDRO-1H-PYRAZOLE[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL]-ACETAMIDE

0.1 g (0.26 mmol) of the compound described in Example 32, 0.06 ml (0.27mmol) diphenyl phosphate azide (DPPA) and 0.04 ml (0.29 mmol)triethylamine are placed in 5 ml dimethylacetamide and stirred for 2hours at 50° C. 0.05 g (0.29 mmol) p-toluenesulphonic acid and 0.10 mlof water are added and the mixture is stirred for 16 hours at 50° C.Then the reaction mixture is purified by chromatography, correspondingfractions are combined and concentrated by evaporation. The residue iscrystallised from ethyl acetate/petroleum ether. Yield: 0.02 g

EXAMPLE 35N-(3-AMINO-1-PHENYL-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL)-ACETAMIDE

Analogously to Example 34, 0.5 g product is obtained from 1.5 g of theacid described in Example 33, 1 ml (4.6 mmol) DPPA and 0.6 ml (4.4 mmol)triethylamine in 20 ml dimethylacetamide and subsequent reaction with 2g p-toluenesulphonic acid and 10 ml of water.

EXAMPLE 36N-[1-(2-CHLOROPHENYL)-3-(3-ISOPROPYL-UREIDO)-4,5-DIHYDRO-1H-PYRAZOLE[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL]-ACETAMIDE

1.0 g (3.1 mmol) of the compound described in Example 35 and 1.0 ml(12.1 mmol) pyridine are suspended in 10 ml dichloromethane and 2 ml oftetrahydrofuran and combined with a solution of 0.8 g (4.0 mmol)4-nitrophenyl chloroformate in 5 ml dichloromethane. The mixture isstirred for 0.5 hours at ambient temperature. 1.8 ml of this solution iscombined with 0.05 ml (0.53 mmol) isopropylamine. It is stirred for 16hours at ambient temperature, then extracted with dichloromethane andwater. The organic phase is dried and evaporated to dryness. The residueis purified by chromatography, corresponding fractions are combined andconcentrated by evaporation. The residue is dissolved in water, madebasic with sodium hydrogen carbonate solution and precipitated crystalsare suction filtered. Yield: 0.010 g

EXAMPLE 37N-[1-(2-CHLORO-PHENYL)-3-(3-METHYL-UREIDO)-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL]-ACETAMIDE

Analogously to Example 36 the desired product is obtained by usingmethylamine.

EXAMPLE 38 ISOPROPYL[7-ACETYLAMINO-1-(2-CHLOROPHENYL)-4,5-DIHYDRO-1H-PYRAZOLE[3′,4′:3,4]BENZO[1,2-d]THIAZOLE-73-YL]-CARBAMATE

10 g (25 mmol) of the compound described in Example 32, 6.0 ml (27 mmol)diphenyl phosphate azide (DPPA) and 4.0 ml (29 mmol) triethylamine areplaced in 80 ml dimethylacetamide and stirred for 2 hours at 50° C. 9 mlof this solution are combined with 2 ml isopropanol and stirred for 48hours at 50° C. Then the mixture is diluted with dichloromethane, thenwashed with potassium hydrogen sulphate solution and sodium hydrogencarbonate solution. The organic phase is dried and evaporated todryness. The residue is dissolved in dichloromethane and shaken with 0.3g anhydride catching resin (MP anhydride resin) for 3 hours. Then theresin is suction filtered, washed with dichloromethane and the organicphase is concentrated by evaporation. The residue is purified bychromatography, corresponding fractions are combined and concentrated byevaporation. Yield: 0.09 g (m.p.: 196° C.)

EXAMPLE 39N-[1-(2-CHLORO-PHENYL)-3-(MORPHOLINE-4-CARBONYL)-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL]-ACETAMIDE

0.1 g (0.26 mmol) of the compound described in Example 32 are placed in5 ml dichloromethane and 0.1 g (0.28 mmol) HATU(o-7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate)are added. Then the mixture is combined with 0.09 ml (0.53 mmol)diisopropylethylamine and 0.03 ml (0.28 mmol) morpholine. The reactionmixture is stirred for 4 hours at ambient temperature, then extractedwith dichloromethane and water. The organic phase is dried andevaporated to dryness. The residue is purified by chromatography.Corresponding fractions are combined, concentrated by evaporation,dissolved in water and made basic with sodium hydrogen carbonatesolution. The precipitated solid is suction filtered and dried. Yield:0.02 g

EXAMPLE 407-ACETYLAMINO-1-PHENYL-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOLE-3-CARBOXYLICACID (2-HYDROXY-ETHYL)-METHYLAMIDE

0.09 g (0.25 mmol) of the compound described in Example 33 are placed in5 ml of dimethylformamide, and 0.1 ml (0.75 mmol) triethylamine and 0.1g (0.25 mmol)(dimethylamino-pentafluorophenyloxymethylene)-dimethyl-ammonium-hexafluorophosphateare added. The mixture is stirred for 0.1 hours at ambient temperature,then 0.02 g (0.25 mmol) 2-methylamino-ethanol are added. The reactionmixture is stirred for 16 hours at ambient temperature and 24 hours at70° C. Then it is concentrated by evaporation, the residue is purifiedby chromatography. Corresponding fractions are combined andfreeze-dried. Yield: 0.04 g

EXAMPLE 41 ETHYL7-ACETYLAMINO-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOLE-3-CARBOXYLATE

Analogously to Example 16.4 g product are obtained from 10 g (32 mmol)intermediate compound 8 and 1.7 g (33 mmol) hydrazine-hydrate.

EXAMPLE 42N-[1-(2-CHLORO-PHENYL)-3-(1-METHYL-1H-IMIDAZOL-4-YL)-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL]-ACETAMIDEEXAMPLE 43N-[2-(2-CHLORO-PHENYL)-3-(1-METHYL-1H-IMIDAZOL-4-YL)-4,5-DIHYDRO-2H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL]-ACETAMIDE

Analogously to Example 1, 100 mg (M.p.: >300° C., Example 42) and 4 mg(Example 43) are obtained from 0.25 g (0.8 mmol) intermediate compound11 and 0.14 g (0.8 mmol) 2-chloro-phenylhydrazine-hydrochloride afterpurification by column chromatography.

EXAMPLE 44N-[1-(2-CHLORO-PHENYL)-3-ISOPROPYL-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL]-ACETAMIDE

Analogously to Example 1, 0.2 g product are obtained from 0.25 g (0.9mmol) intermediate compound 12 and 0.16 g (0.9 mmol)2-chloro-phenylhydrazine-hydrochloride after purification by columnchromatography.

EXAMPLE 454-(7-ACETYLAMINO-3-ISOPROPYL-4,5-DIHYDRO-PYRAZOLO-[3′,4′:3,4]BENZO[1,2-d]THIAZOL-1-YL)-3-CHLORO-N-(1-METHYL-PIPERIDIN-4-YL)-BENZAMIDE

Analogously to Example 1, 0.68 g product, the ester function of which issaponified with 0.1 g lithium hydroxide analogously to Example 26, isobtained from 3.25 g (10.7 mmol) intermediate compound 12 and 2.14 g(10.7 mmol) methyl 3-chloro-4-hydrazinebenzoate. Then 40 mg of the acidobtained are subjected to amide coupling with methylaminopiperidine asdescribed in Example 26.

EXAMPLE 46N-[1-(2-CHLORO-PHENYL)-3-METHYL-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL]-ACETAMIDE

Analogously to Example 10.16 g product are obtained from 0.25 g (1.0mmol) intermediate compound 10 and 0.18 g (1.0 mmol)2-chloro-phenylhydrazine-hydrochloride.

EXAMPLE 47N-[1-(2-CHLORO-PHENYL)-3-PYRIDIN-3-YL-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL]-ACETAMIDE

Analogously to Example 10.06 g product are obtained from 0.1 g (0.3mmol) intermediate compound 9 and 0.06 g (0.3 mmol)2-chloro-phenylhydrazine-hydrochloride after purification by columnchromatography.

EXAMPLE 48N-[1-(2-CHLORO-PHENYL)-3-PHENYL-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL]-ACETAMIDE

Analogously to Example 1, 0.2 g product (M.p.: 232-234° C.) are obtainedfrom 0.3 g (1.0 mmol) intermediate compound 5 and 0.18 g (1.0 mmol)2-chloro-phenylhydrazine-hydrochloride.

EXAMPLE 49N-[1-(2-CHLORO-PHENYL)-3-PHENYL-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL]-4-DIMETHYLAMINO-BUTYRAMIDE

A mixture of 0.5 g (1.2 mmol) of the compound obtained in Example 48 in5 ml of water and 5 ml hydrochloric acid is refluxed for 2 hours. Thesolid precipitated after the solution is cooled is suction filtered anddried. Yield: 0.4 g (M.p.: 182-185° C.)

0.1 g of the intermediate compound described previously are suspended in5 ml dichloromethane, combined with 0.16 ml (1.2 mmol) triethylamine andstirred for 15 minutes at ambient temperature, forming a solution. Thisis heated to 40° C. and 0.17 g (0.9 mmol) 4-dimethylamino-butanoic acidchloride are added. The reaction mixture is stirred for 3 hours at 40°C. and then washed with 5% sodium carbonate solution and water. Theorganic phase is dried, evaporated down and the residue isrecrystallised from isopropanol. Yield: 11 mg (M.p. 290-291° C.)

EXAMPLE 50N-[3-(1H-IMIDAZOL-4-YL)-1-(2-TRIFLUOROMETHYL-PHENYL)-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL]-ACETAMIDE

Analogously to Example 11.26 g intermediate product are obtained from1.36 g (3.1 mmol) intermediate compound 17 and 0.55 g (3.1 mmol)2-trifluoromethyl-phenylhydrazine. Of this, 75 mg (0.13 mmol) aresuspended in 0.65 ml (0.65 mmol) tetrabutylammonium fluoride solution (1M in THF) and refluxed for 5.5 hours. The solution is combined with 5 mlpH 7-buffer solution, diluted with 10 ml of water and extracted withethyl acetate. The organic phase is washed with buffer solution, driedand evaporated to dryness. The residue is purified by chromatography,the corresponding fraction is stirred out with diethyl ether. Yield: 5mg (M.p.: >300° C.)

EXAMPLE 51N-[1-(2-CHLORO-PHENYL)-3-(1H-IMIDAZOL-4-YL)-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL]-ACETAMIDE

Analogously to Example 1, 0.5 g intermediate product are obtained from0.6 g (1.4 mmol) intermediate compound 17 and 0.3 g (1.4 mmol)2-chlorophenylhydrazine hydrochloride. This is converted into thedesired product with 1.7 ml (1.7 mmol) tetrabutylammonium fluoridesolution (1 M in THF) as described in Example 50. Yield: 35 mg (M.p.:287-288° C.)

EXAMPLE 52(R)—N-[1-(2-CHLORO-PHENYL)-3-(TETRAHYDRO-FURAN-2-YL)-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL]-ACETAMIDE

Analogously to Example 10.23 g product are obtained from 0.25 g (0.8mmol) intermediate compound 14 and 0.15 g (0.8 mmol)2-chloro-phenylhydrazine-hydrochloride after purification by columnchromatography.

EXAMPLE 53(R)-4-[7-ACETYLAMINO-3-(TETRAHYDRO-FURAN-2-YL)-4,5-DIHYDRO-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-1-YL]-3-CHLORO-N-PYRIDIN-4-YLMETHYL-BENZAMIDE

Analogously to Example 11.16 g product, the ester function of which issaponified with 0.2 g lithium hydroxide analogously to Example 26, isobtained from 1.25 g (4.1 mmol) intermediate compound 14 and 0.82 g (4.1mmol) methyl 3-chloro-4-hydrazine benzoate. Then 50 mg of the acidobtained are subjected to amide coupling with 4-picolylamine asdescribed in Example 26.

EXAMPLE 54(S)—N-[1-(2-CHLORO-PHENYL)-3-(TETRAHYDRO-FURAN-2-YL)-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL]-ACETAMIDE

Analogously to Example 10.08 g product are obtained from 0.1 g (0.3mmol) intermediate compound 15 and 0.05 g (0.3 mmol)2-chloro-phenylhydrazine-hydrochloride after purification by columnchromatography.

EXAMPLE 55N-[1-(2-CHLORO-PHENYL)-3-TRIMETHYLSILANYLETHYNYL-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL]-ACETAMIDE

Analogously to Example 10.02 g product are obtained from 0.1 g (0.3mmol) intermediate compound 16 and 0.06 g (0.3 mmol)2-chlorophenylhydrazine-hydrochloride after purification by columnchromatography.

EXAMPLE 56N-[3-ETHYNYL-1-(2-TRIFLUOROMETHYL-PHENYL)-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL]-ACETAMIDE

Analogously to Example 10.05 g product are obtained from 0.3 g (0.9mmol) intermediate compound 16 and 0.16 g (0.9 mmol)2-(trifluoromethyl)phenylhydrazine after purification by columnchromatography. Of this, 0.04 g are placed in 5 ml THF and combined with0.1 ml (0.1 mmol) tetrabutylammonium fluoride solution (1 M in THF). Themixture is stirred for 0.5 hours at ambient temperature and then wateris added. The aqueous phase is extracted with ethyl acetate, the organicphase is washed with water and 1 N hydrochloric acid. The organic phaseis dried and evaporated to dryness. The residue is purified bychromatography. Yield: 0.012 g

EXAMPLE 57N-(1-PHENYL-3-TRIFLUOROMETHYL-4,5-DIHYDRO-1H-PYRAZOLO[3′,4′:3,4]BENZO[1,2-d]THIAZOL-7-YL)-ACETAMIDE

Analogously to Example 10.04 g product are obtained from 0.3 g (1.0mmol) intermediate compound 19 and 0.15 g (1.0 mmol)phenylhydrazine-hydrochloride.

EXAMPLE 58 N-[4-(4-CHLORO-PHENYL)-4,7-DIHYDRO-3-THIA-1,4,5-TRIAZA-CYCLOPENTA[A]PENTALEN-2-YL]-ACETAMIDE

0.50 g (1.56 mmol) intermediate compound 22 are suspended in 8 mlglacial acetic acid, combined with 0.34 g (1.88 mmol)4-chlorophenylhydrazine-hydrochloride. The mixture is stirred for 1.5hours at 60° C., then cooled to ambient temperature. After the additionof 50 ml of water a precipitate is formed. This is stirred for 0.1 hoursat 5° C., suction filtered and recrystallised from methanol. Yield: 0.19g (m.p.: 296-305° C.)

EXAMPLE 594-PHENYL-4,7-DIHYDRO-3-THIA-1,4,5-TRIAZA-CYCLOPENTA[A]PENTALEN-2-YL-AMINE

2.9 g (8.71 mmol)N-(4-phenyl-4,7-dihydro-3-thia-1,4,5-triaza-cyclopenta[A]pentalen-2-yl)-acetamide(prepared analogously to Example 58 from intermediate compound 22) aresuspended in 20 ml of water and 20 ml 32% hydrochloric acid and refluxedfor 2 hours with stirring. After cooling to ambient temperature themixture is extracted with diethyl ether and the aqueous phase is madebasic. The precipitate formed is stirred for 0.25 hours at 5° C.,suction filtered and dried. The crude product is suspended in 150 ml oftetrahydrofuran and combined with 5 ml of conc. hydrochloric acid, thenstirred for 16 hours at 60° C. After cooling to 5° C. the precipitate issuction filtered and dried.

Yield: 1.8 g

EXAMPLE 604-o-TOLYL-3A,4,7,7A-TETRAHYDRO-3-THIA-1,4,5-TRIAZA-CYCLOPENTA[A]PENTALEN-2-YLAMINE

Analogously to Example 5914 mg product are obtained from 140 mg (0.5mmol)N-(4-o-tolyl-4,7-dihydro-3-thia-1,4,5-triaza-cyclopenta[A]pentalen-2-yl)-acetamide(prepared analogously to Example 58) in 1 ml of water and 1 mlhydrochloric acid after purification by column chromatography.

EXAMPLE 61 4-DIMETHYLAMINO-N-(4-PHENYL-4,7-DIHYDRO-3-THIA-1,4,5-TRIAZA-CYCLOPENTA[A]PENTALEN-2-YL)-BUTANOIC ACID AMIDE

0.5 g (1.72 mmol) of the compound described under Example 59 aresuspended in 25 ml dichloromethane, combined with 0.8 ml (6.02 mmol)triethylamine and refluxed. 0.8 g (4.30 mmol) 4-dimethylamine-butyricacid chloride-hydrochloride in 5 ml dichloromethane are added dropwisewithin 0.1 hours and the reaction mixture is refluxed for 16 hours.After cooling to ambient temperature the precipitate is suction filteredand the filtrate is washed with 5% sodium hydrogen carbonate solutionand water. The organic phase is dried and evaporated to dryness. Theresidue is triturated with diethyl ether and suction filtered. Yield:0.2 g (m.p.: 218-222° C.)

EXAMPLE 62 N-[4-(2-CHLORO-PHENYL)-4,7-DIHYDRO-3-THIA-1,4,5-TRIAZA-CYCLOPENTA[A]PENTALEN-2-YL]-4-DIMETHYLAMINO-BUTANOICACID AMIDE

Analogously to Example 59, 2.5 g of a compound are obtained from 3.9 g(11.7 mmol)4-(2-chloro-phenyl)-4,7-dihydro-3-thia-1,4,5-triaza-cyclopenta[a]pentalen-2-ylamine(prepared analogously to Example 58), of which 0.7 g (1.7 mmol) arereacted as in Example 61 to form 0.2 g product (m.p.: 167-170° C.).

EXAMPLE 63 PIPERIDINE-1-CARBOXYLICACID-(4-PHENYL-4,7-DIHYDRO-3-THIA-1,4,5-TRIAZA-CYCLOPENTA[A]PENTALEN-2-YL)-AMIDE

A suspension of 2.3 g (8 mol) of the compound obtained under Example 59in 60 ml of pyridine is heated to 50° C., then combined with 1.6 ml (10mmol) ethyl chlorothioformate. The reaction mixture is stirred for 12hours at 70° C., then stirred into 600 ml of water. The precipitateformed is suction filtered and washed with water and ether. Yield: 2.3 g(M.p.: 142-145° C.)

In a sealable pressurised glass tube 0.3 g (0.7 mmol) of the compounddescribed previously are suspended in 8 ml of ethanol, combined with 1ml (10.5 mmol) piperidine and refluxed for 16 hours with stirring. Aftercooling to ambient temperature the reaction mixture is concentrated byevaporation. The crude product is filtered through silica gel. Theresidue is triturated with 20 ml of water and 5 drops of acetonitrile,suction filtered and dried. Yield: 0.07 g (m.p.: 120-125° C.)

EXAMPLE 64N-[8-(4-HYDROXY-PHENYL)-4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLIN-2-YL]-ACETAMIDE

2.7 g (11.3 mmol) intermediate compound 2 and 1.7 g (12.6 mmol)4-hydroxybenzamidine are suspended in 6 ml of pyridine and heated to100° C. for 2 hours. The reaction mixture is combined with ether and theprecipitate formed is stirred with methanol. Yield: 2.1 g

EXAMPLE 65 4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLINE-2,8-DIAMINE

10 g (42 mmol) intermediate compound 2, 4 g (42 mmol)guanidine-hydrochloride and 2.2 g (21 mmol) sodium carbonate aresuspended in 30 ml amyl alcohol and refluxed for 1 hour using the waterseparator. The reaction mixture is evaporated down, the residue isdistilled off with xylene several times and then purified bychromatography. The product is taken up in methanol and precipitatedwith methanolic hydrochloric acid as the hydrochloride. Yield: 1.2 g(M.p.: 293-300° C.)

EXAMPLE 66N-(8-ACETYLAMINO-4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLIN-2-YL)-ACETAMIDE

0.5 g (1.7 mmol) of the compound described in Example 65 and 0.4 g (4.6mmol) sodium acetate are suspended in 15 ml acetic anhydride and stirredfor 2 hours at 100° C. The mixture is cooled to 5° C., the resultingsolid is suction filtered and washed with water. The crude product isstirred with methanol. Yield: 0.4 g (M.p.: >310° C.)

EXAMPLE 67N-(6-OXO-8-PHENYL-4,5,6,7-TETRAHYDRO-THIAZOLO[4,5-h]QUINAZOLIN-2-YL)-ACETAMIDE

In a pressurised glass tube 0.1 g (0.35 mmol) intermediate compound 18and 0.1 g (0.83 mmol) benzamidine are placed in 1 ml of pyridine andheated to 160° C. for 4 hours. The solvent is concentrated byevaporation, the residue is stirred with hot ethanol and suctionfiltered. Yield: 14 mg

EXAMPLE 68N-(8-ETHYLSULPHANYL-4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLIN-2-YL)-ACETAMIDE

10.0 g (42 mmol) intermediate compound 2 and 14.6 g (80 mmol)ethylisothiourea-hydrobromide are suspended in 20 ml of pyridine andthen stirred for 3 hours at 110° C. After cooling to ambient temperaturethe reaction mixture is triturated with a little methanol, suctionfiltered and dried. Yield: 10.2 g

EXAMPLE 69N-(8-ETHANESULPHONYL-4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLIN-2-YL)-ACETAMIDE

10.6 g (34.6 mmol) of the compound prepared under Example 68 aredissolved in 100 ml dichloromethane, 17.0 g (75.9 mmol)m-chloroperbenzoic acid are added and the mixture is then stirred for 24hours at ambient temperature. The reaction mixture is diluted withdichloromethane and extracted with sodium carbonate solution. Theorganic phase is washed with water, dried and evaporated to dryness.Yield: 8.8 g

EXAMPLE 70 TERT-BUTYL[1-(2-ACETYLAMINO-4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLIN-8-YL)-PIPERIDIN-3-YLMETHYL]-CARBAMATE

0.2 g (0.6 mmol) of the compound prepared under Example 69 and 0.25 g(1.2 mmol) tert-butyl piperidin-3-ylmethyl-carbamate are placed in 2 mlN-methyl-pyrrolidine and refluxed for 24 hours with stirring. Then thereaction mixture is combined with dilute potassium carbonate solutionand dichloromethane and extracted. The organic phase is washed withwater, dried and evaporated to dryness. The residue is purified bychromatography. Yield: 0.03 g (m.p.: 250-255° C.)

EXAMPLE 71 8-PHENYL-4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLIN-2-YLAMINE

9.0 g (28 mmol)N-(8-phenyl-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl)-acetamide(prepared analogously to Example 64) are refluxed for 2 hours in 130 mlsemi-concentrated hydrochloric acid. After cooling the reaction mixtureis made basic, the precipitate formed is suction filtered and dried.Yield: 7.3 g

EXAMPLE 72N⁸,N⁸-DIMETHYL-4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLINE-2,8-DIAMINE

Analogously to Example 710.14 g product (M.p.: 292-295° C.) may beobtained from 0.20 g (0.7 mmol)N-(8-dimethylamino-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl)-acetamide(obtained analogously to Example 58).

EXAMPLE 73N-(8-PHENYL-4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLIN-2-YL)-PROPIONIC ACIDAMIDE

0.3 g (1.1 mmol) of the compound obtained in Example 71 are suspended in15 ml dichloromethane, combined with 0.4 ml (2.5 mmol) triethylamine andgently refluxed. 0.2 ml (2.3 mmol) propionic acid chloride are added andthe mixture is refluxed for 5 hours with stirring. After cooling toambient temperature the reaction solution is washed with sodium hydrogencarbonate and water, dried and evaporated to dryness. The residue isstirred with diethyl ether and suction filtered. Yield: 0.2 g (m.p.:274-275° C.)

EXAMPLE 744-DIMETHYLAMINO-N-(8-PHENYL-4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLIN-2-YL)-BUTYRICACID AMIDE

Analogously to Example 73, 0.03 g product are obtained from 0.15 g (0.5mmol) of the compound obtained in Example 71, 1 ml triethylamine and 0.2g (1.3 mmol) 4-dimethylamine-butyric acid chloride-hydrochloride.

EXAMPLE 75N-(8-PHENYL-4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLIN-2-YL)-FORMAMIDE

0.2 g (0.71 mmol) of the compound described in Example 71 and 2.5 ml(22.7 mmol) phenyl formate are placed in a pressurised glass tube andstirred for 16 hours at 80° C. Then the reaction mixture is concentratedby evaporation and the residue is triturated with diethyl ether/ethanol.Yield: 0.17 g (m.p.: 304-306° C.)

EXAMPLE 76 MORPHOLINE-4-CARBOXYLICACID-(8-PHENYL-4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLIN-2-YL)-AMIDE

2.5 g (8.9 mmol) of the compound obtained in Example 71 are placed in 50ml of pyridine and heated to 50° C. 1.5 ml (13.8 mmol) ethylchlorothioformate are added and the mixture is stirred for 20 hours at50° C. After cooling to ambient temperature the reaction solution isadded to water and extracted with dichloromethane. The organic phase isdried and evaporated to dryness. The residue is crystallised withdiethyl ether. Yield: 1.0 g

0.2 g (0.54 mmol) of the intermediate described above and 0.1 g (1.15mmol) morpholine in 5 ml of ethanol are placed in a pressurised glasstube and then stirred for 16 hours at 80° C. After cooling to ambienttemperature the precipitate formed is suction filtered and dried. Yield:0.14 g (m.p.: 165-168° C.)

EXAMPLE 774-(2-ACETYLAMINO-4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLIN-8-YL)-N,N-DIMETHYL-BENZAMIDE

1.0 g (3.8 mmol) of the intermediate compound 2 and 0.8 g (3.1 mmol)carbamimidoyl-benzoic acid-methanesulphonate are placed in 5 ml ofpyridine and heated to 180° C. for 5 hours. After cooling to ambienttemperature the reaction mixture is stirred with ethanol and suctionfiltered. Yield: 0.6 g

0.1 g (0.27 mmol) of the previously prepared compound and 0.1 gO-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate(TBTU) are placed in 2 ml of dimethylformamide, combined with 0.2 mldiisopropylethylamine and stirred for 0.5 hours at ambient temperature.0.2 ml (4.0 mmol) dimethylamine (2 M in THF) are added and the mixtureis stirred for a further 16 hours at ambient temperature. The resultingsuspension is dissolved with dimethylformamide, then purified byRP-HPLC. Corresponding fractions are combined and freeze-dried. Yield:0.04 g (m.p.: >300° C.)

EXAMPLE 78N-[8-(2-OXO-PYRROLIDIN-1-YL)-4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLIN-2-YL]-ACETAMIDE

2.0 g (8.4 mmol) intermediate compound 2 and 2.4 g (16.8 mmol)4-guanidine-butyric acid in 30 ml of pyridine are placed in apressurised glass tube and then heated to 190° C. for 20 hours. Thereaction mixture is concentrated by evaporation, the residue is boiledwith methanol and insoluble constituents are filtered off. The crudeproduct is precipitated from the mother liquor in the form of thehydrochloride, suction filtered and dried. The solid is purified bycolumn chromatography. Yield: 0.02 g (m.p.: >160° C.)

EXAMPLE 79N-[8-(3-AMINOMETHYL-PIPERIDIN-1-YL)-4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLIN-2-YL]-ACETAMIDE

0.05 g (0.1 mmol) of the compound described under Example 70 aredissolved in 5 ml ethereal hydrochloric acid and stirred for 16 hours atambient temperature. The resulting solid is suction filtered, washedwith diethyl ether and dried. Yield: 0.035 g

EXAMPLE 80N-{8-[3-(ISOPROPYLAMINO-METHYL)-PIPERIDIN-1-YL]-4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLIN-2-YL}-ACETAMIDE

0.2 g (0.5 mmol) of the compound obtained in Example 79, 0.05 ml (0.6mmol) acetone and 0.02 g (0.5 mol) sodium borohydride are dissolved inmethanol and stirred for 0.5 hours at 40° C. The same amounts of acetoneand sodium borohydride are added again and the mixture is stirred for afurther 16 hours at ambient temperature. Then the reaction mixture isconcentrated by evaporation, the residue is extracted withdichloromethane and water. The organic phase is dried and evaporated todryness. The crude product is triturated with diethyl ether and suctionfiltered. Yield: 0.040 g

EXAMPLE 81 N-{8-[ACETYL-(2-DIMETHYLAMINO-ETHYL)-AMINO]-4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLIN-2-YL}-ACETAMIDE

0.4 g (1.2 mmol) of the compound obtained under Example 69 and 0.4 ml(4.5 mmol) N¹,N¹-dimethylethane-1,2-diamine are placed in 5 mlN-methylpyrrolidine and stirred for 48 hours at 90° C. The reactionmixture is extracted with dichloromethane and 10% potassium carbonatesolution. The organic phase is dried and evaporated to dryness. Yield:0.08 g

0.08 g (0.28 mmol) of the compound described previously are dissolved in5 ml (49 mmol) acetic anhydride and stirred for 1 hour at 140° C. Thereaction mixture is concentrated by evaporation, the residue is stirredwith acetonitrile and suction filtered. Yield: 0.07 g

EXAMPLE 82 TERT-BUTYL(2-ACETYLAMINO-4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLIN-8-YL)-PROP-2-YNYL-CARBAMATE

0.34 g (2.2 mmol) tert-butyl prop-2-ynyl-carbamate are placed in 3 ml oftetrahydrofuran and cooled to −30° C. 2.3 ml (4.4 mmol) 2 Misopropylmethyl-magnesium chloride solution in tetrahydrofuran areslowly added dropwise and the mixture is stirred for 0.5 hours. Then asolution of 0.34 g (1.0 mmol) of the compound described in Example 69 in4 ml of tetrahydrofuran is added at −10° C. and the mixture is stirredfor 4 hours, while heating to ambient temperature. The reaction mixtureis extracted with water and dichloromethane, the organic phase is driedand evaporated to dryness. The residue is triturated with diethyl ether.Yield: 0.18 g

EXAMPLE 83N-(8-PROP-2-YNYLAMINO-4,5-DIHYDRO-THIAZOLO[4,5-h]QUINAZOLIN-2-YL)-ACETAMIDE

0.05 g (0.13 mmol) of the compound obtained in Example 82 are dissolvedin 5 ml ethereal hydrochloric acid and stirred for 16 hours at ambienttemperature. The resulting solid is suction filtered, triturated withdiethyl ether/acetone 9:1 and suction filtered again. Yield: 0.03 g

EXAMPLE 84 N-[1-(4-METHOXY-PHENYL)-1,4,5,6-TETRAHYDRO-9-THIA-1,2,7-TRIAZA-CYCLOPENTA[E]AZULEN-8-YL]-ACETAMIDE

A solution of 0.25 g (1 mmol) intermediate compound 23 and 0.18 mg (1mmol) 4-methoxyphenylhydrazine-hydrochloride in 5 ml glacial acetic acidis heated to 60° C. for 2 h. The mixture is combined with water andextracted three times with ethyl acetate. The combined organic phasesare dried over magnesium sulphate and evaporated down. The residue ispurified first of all by column chromatography(eluant:dichloromethane/methanol 95:5), then by RP-HPLC.

Yield: 0.07 g

EXAMPLE 85N-(8-NITRO-4,5-DIHYDRO-3H-1λ⁴-NAPHTHO[2,1-d]THIAZOL-2-YL)-ACETAMIDE

0.8 g (10.0 mmol) sodium acetate and 1.9 g (9.40 mmol)7-nitro-3,4-dihydro-1H-naphthalen-2-one (prepared according to D. E.Nichols et al., J. Med. Chem. 1989, 32, 2128-2134) are dissolved in 40ml acetic acid and cooled to 15° C. 0.5 g (3.19 mmol) bromine are addedand the mixture is stirred for 0.1 hours, until the bromine has finishedreacting completely. Then 0.8 g (10.5 mmol) thiourea are added. Thereaction mixture is heated to 60° C. for 0.25 hours, then suctionfiltered and washed. The crystals are recrystallised from ethanol.Yield: 0.75 g (M.p.: 247-248° C.) 0.75 g (3.0 mmol) of the compounddescribed previously are placed in 5 ml (49 mmol) acetic anhydride andrefluxed for 0.1 hours. After cooling to ambient temperature theprecipitate formed is suction filtered, washed with ethyl acetate anddiethyl ether and dried. Yield: 0.8 g (M.p.: >315° C.)

EXAMPLE 86N-(8-ACETYLAMINO-4,5-DIHYDRO-3H-1λ⁴-NAPHTHO[2,1-d]THIAZOL-2-YL)-ACETAMIDE

0.5 g (1.7 mmol) of the compound described in Example 85 are suspendedin 10 ml acetic acid and combined with 2 g iron powder. The reactionmixture is heated to 70° C. and stirred for 0.1 hours. Then it issuction filtered and the mother liquor is concentrated by evaporation.The residue is combined with water, the precipitate is suction filtered,washed and dried. Yield: 0.4 g

0.1 g (0.4 mmol) of the compound described previously, 0.1 g (1.0 mmol)acetic anhydride and 0.1 ml triethylamine are placed in 5 mldichloromethane and stirred for 1 hour at ambient temperature. Then thereaction mixture is washed with 2 N hydrochloric acid and 2 N sodiumhydroxide solution. The organic phase is dried and evaporated todryness. The residue is crystallised from ethyl acetate. Yield: 0.07 g(m.p.: 181-183° C.)

EXAMPLE 87N-(2-ACETYLAMINO-4,5-DIHYDRO-NAPHTHO[2,1-d]THIAZOL-8-YL)-ISOBUTYRIC ACIDAMIDE

Analogously to Example 860.075 g product (M.p.: 272-274° C.) may beobtained from 0.1 g (0.4 mmol) of the intermediate described therein,0.045 g (0.4 mmol) isobutyric acid chloride and 0.1 ml triethylamine in5 ml dichloromethane.

EXAMPLE 88N-(8-ISOPROPYLAMINO-4,5-DIHYDRO-3H-1λ⁴-NAPHTHO[2,1-d]THIAZOL-2-YL)-ACETAMIDE

0.15 g (0.58 mmol) of the intermediate described in Example 86, 1.0 g(17.2 mmol) acetone and 0.4 g sodium triacetoxyborohydride are placed in10 ml dichloromethane and stirred for 4 hours at ambient temperature.The reaction mixture is combined with 50 ml of water and 2 g potassiumcarbonate, the organic phase is separated off, dried and evaporated todryness. The residue is purified by chromatography, then crystallisedfrom diethyl ether. Yield: 0.11 g (m.p.: 183-184° C.)

EXAMPLE 89 N-[5-(2-CHLORO-PHENYL)-8H-3-THIA-1,4,6-TRIAZA-CYCLOPENTA[A]INDEN-2-YL]-ACETAMIDE

350 mg (1.56 mmol) intermediate compound 22 and 298 mg (1.56 mmol)2-chlorobenzamidine are suspended in 1.5 mL pyridine and heated to 160°C. for 1 hour. The reaction mixture is evaporated down and purified byRP-HPLC. Yield: 14 mg (m.p.: 257° C.)

EXAMPLE 90N-(5-MORPHOLIN-4-YL-8H-3-THIA-1,4,6-TRIAZA-CYCLOPENTA[A]INDEN-2-YL)-ACETAMIDE

350 mg (1.56 mmol) intermediate compound 22 and 260 mg (1.57 mmol)morpholinecarboxamidine are suspended in 1.5 mL pyridine and heated to160° C. for 1 hour. The reaction mixture is evaporated down and purifiedby RP-HPLC.

Yield: 11 mg (m.p.: >300° C.)

EXAMPLE 91N-(5-PHENYL-8H-3-THIA-1,4,6-TRIAZA-CYCLOPENTA[A]INDEN-2-YL)-ACETAMIDE

350 mg (1.56 mmol) intermediate compound 22 and 190 mg (1.58 mmol)benzamidine are suspended in 1.5 mL pyridine and heated to 160° C. for 1hour. The reaction mixture is evaporated down and purified by RP-HPLC.Yield: 16 mg (m.p.: >300° C.)

Some compounds which may be prepared by one of the methods of synthesisdescribed above are hereinafter listed by way of example. All themelting points (m_(p)) are given in ° C. In order to determine theinhibitory activity of the compounds on PI3Kγ, an in-vitro kinase assayis set up which is based on the transfer of the terminal γ-phosphate ofATP to phosphatidylinositol-4,5-bisphosphate (PIP₂). The enzyme activityused is the Gβ₁γ₂-His stimulated PI3Kγ. The expression and purificationof Gβ₁γ₂-His and p101-GST/p110γ from Sf9-cells (Spodoptera frugiperda 9)has already been described (Maier et al., J. Biol. Chem. 1999 (274)29311-29317).

The kinase assay is carried out in white 384-well flat-bottomed dishes.Each well contained 5 μl of the compound to be tested which had beendissolved in assay buffer (40 mM Hepes, pH 7.5, 100 mM NaCl, 1 mM EGTA,1 mM β-glycerophosphate, 1 mM DTT, 7 mM MgCl₂ and 0.1% BSA; 6% DMSO). 15μl of lipid vesicles containing 10 ng of PI3Kγ and 31.5 ng of Gβ₁γ₂-Hiswere added in each case. The lipid vesicles in turn were generated bysuspending PIP₂ (0.35 μg/well), phosphatidyl ethanolamine (3.75μg/well), phosphatidyl serine (3.5 μg/well), sphingomyelin (0.35μg/well) and phosphatidyl choline (1.6 μg/well) in lipid buffer (assaybuffer without DMSO) by ultrasound treatment. After the addition of thelipid vesicles the reaction is started by the addition of 10 μl reactionbuffer (40 mM Hepes, pH 7.5, 100 mM NaCl, 1 mM EGTA, 1 mMβ-glycerophosphate, 1 mM DTT, 7 mM MgCl₂ and 0.1% BSA; 1 μM ATP and 0.2μCi [γ-³³P]-ATP). The reaction mixture is incubated in this way for 1 hand then stopped by the addition of a suspension of 0.12 mg LEADseekerbeads (Amersham Biosciences) in stop buffer (40 mM Hepes, pH 7.5, 100 mMNaCl, 1 mM EGTA, 12 mM EDTA, 1 mM β-glycerophosphate, 1 mM DTT). After 1minute's centrifugation at 500×g the plates were read and analysed usinga LEADseeker apparatus. All the compounds shown have an IC₅₀ value ofless than 800 nM in the test.

EXAMPLES A

R^(a) R^(b) R^(c) m_(p) 1.

H

2.

H

3.

—CH₃

>280 4.

258-260 5.

282-283 6.

286-288 7.

280-282 8.

>300 9.

261-263 10.

295-298 11.

>300 12.

>300 13.

297-299 14.

>300 15.

>300 16.

>300 17.

259-261 18.

>300 19.

H

20.

H

214-216 21.

H

227-229 22.

H

244-246 23.

H

211-213 24.

H

242-244 25.

H

270-273 26.

H

251-253 27.

H

28.

277-290 Decomp. 29.

113-120 Decomp. 30.

H

31.

H

32.

H

  236-237.5 33.

H

298-304 Decomp. 34.

H

303.5-306   35.

H

36.

H

37.

H

>300 38.

H

39.

H

154-157 40.

295-300 41.

H

256-259 42.

H

228-230 43.

H

270-273 44.

H

202-204 45.

H

202-204 46.

H

 >300° 47.

295-305 48.

H

264-266 49.

H

294-296 50.

H

>300 51.

H

52.

 296- >Decomp. 53.

H

233-235 54.

H

234-235 55.

H

56.

H

249-251 57.

H

248-249 58.

H

135-137 59.

H

 239 60.

H

61.

H

62.

H

63.

H

64.

H

65.

H

66.

H

67.

H

68.

H

69.

70.

71.

H

72.

H

255-256 73.

74.

H

75.

H

76.

77.

H

78.

H

79.

H

80.

H

81.

82.

H

83.

84.

H

85.

—CH₃

86.

H

87.

H

88.

H

89.

H

 230 90.

H

  227.4 91.

H

92.

H

93.

94.

H

95.

H

>300 96.

H

97.

98.

H

99.

H

100.

101.

H

102.

H

103.

H

104.

H

105.

H

106.

H

107.

H

108.

H

109.

H

110.

H

111.

H

112.

H

113.

H

114.

—CH₃

115.

H

116.

H

117.

118.

H

119.

120.

H

121.

H

122.

H

280-281 123.

H

 245 124.

H

317-319 125.

H

300-310 126.

H

226-227 127.

H

240-250 128.

H

304-310 129.

H

130.

H

131.

H

132.

H

133.

H

134.

H

135.

H

136.

H

137.

H

138.

H

139.

H

140.

H

141.

H

142.

H

143.

H

144.

H

145.

H

146.

H

147.

H

148.

H

149.

H

150.

H

151.

H

152.

H

153.

H

154.

H

155.

H

156.

H

157.

H

158.

H

159.

  303.1 160.

  281.3 161.

  248.3 162.

163.

164.

H

>300 165.

H

>280 166.

>300 167.

>300 168.

H

248-251 169.

H

242-245 170.

>300 171.

H

 298->300 172.

H

>300 173.

H

209-211 174.

175.

176.

177.

178.

179.

180.

181.

182.

183.

184.

185.

186.

187.

188.

189.

190.

191.

192.

193.

194.

195.

196.

197.

198.

199.

H

200.

H

201.

H

202.

H

203.

H

204.

H

205.

H

206.

H

207.

H

208.

H

209.

H

210.

H

211.

H

212.

H

213.

H

214.

H

215.

H

216.

H

217.

H

218.

H

219.

H

220.

H

221.

H

222.

H

223.

H

224.

H

225.

H

226.

H

227.

H

228.

H

229.

H

230.

H

231.

H

232.

H

233.

H

234.

H

235.

H

236.

H

237.

H

238.

H

239.

H

240.

H

241.

H

242.

H

243.

H

244.

H

245.

H

246.

H

247.

H

248.

H

249.

H

250.

H

251.

H

252.

H

253.

H

254.

H

255.

H

256.

H

257.

H

258.

H

259.

H

260.

H

261.

H

262.

H

263.

H

264.

H

265.

H

266.

H

267.

H

268.

H

269.

H

270.

H

271.

H

272.

H

273.

H

274.

H

275.

H

276.

H

277.

H

278.

H

279.

H

280.

281.

282.

283.

H

284.

H

285.

H

286.

H

287.

H

288.

H

289.

H

290.

H

291.

H

292.

H

293.

H

294.

H

295.

H

296.

H

297.

H

298.

H

299.

H

300.

H

301.

H

302.

H

303.

H

304.

H

305.

H

306.

H

307.

H

308.

H

309.

H

310.

H

311.

H

312.

H

313.

H

314.

H

315.

H

316.

H

317.

H

318.

H

319.

H

320.

H

321.

H

322.

H

323.

H

324.

H

325.

H

326.

H

327.

H

328.

H

329.

H

330.

H

331.

H

332.

H

333.

H

334.

H

335.

H

336.

H

337.

H

338.

H

339.

H

340.

H

341.

342.

H

343.

H

EXAMPLES B

R^(a) R^(b) R^(c) m_(p) 344.

H

>300 345.

H

298-305 346.

H

255-260 347.

H

245-252 348.

H

288-295 349.

H

350.

H

>300 351.

H

296-300 352.

H

292-300 353.

H

>280 354.

H

238-243 355.

H

>300 356.

H

205-210 357.

H

200-204 358.

H

108-115 359.

H

>300 360.

H

175-180 361.

H

172-175 362.

H

220-222 363.

H

>250 364.

H

239-242 365.

H

216-219 366.

H

>300 367.

H

199-201 368.

H

>300 369.

H

246-247

EXAMPLES C

R^(a) R^(b) R^(c) m_(p) 370.

H

>275 371.

H

267-268 372.

H

267-268 373.

H

>295 374.

H

>300 375.

H

>300 376.

H

208-209 377.

H

132-133 378.

H

>300 379.

H

147.4-150   380.

H

  147-149.3 381.

H

263.4-264.5 382.

H

237.9-239.4 383.

H

272-273 384.

H

242-243 385.

H

>300 386.

H

196-199 387.

H

221-222 388.

H

>300 389.

H

231-232 390.

H

>300 391.

H

  234-234.5 392.

H

273-274 393.

H

194-196 394.

H

287.7-289   395.

OH

EXAMPLES D

R^(a) R^(b) R^(c) m_(p) 396.

289-290 397.

>300 398.

399.

400.

>300 401.

>300 402.

EXAMPLES E

R^(a) R^(b) R^(c) m_(p) 403. —CH₃ H

404.

H

405.

H

406.

H

407.

H

408.

H

409.

H

246-247 410.

H

411.

H

412.

H

413.

H

191 414.

H

415.

H

416.

H

EXAMPLES F

R^(a) R^(b) R^(c) m_(p) 417.

H

418.

H

419.

H

420.

H

421.

H

422.

H

423.

H

235-238 424.

H

281-282 425. —CF₃ H

366-370 426.

H

248.4-250.6 427.

H

198-199 428. —CH₃ H

224-225 429.

H

 94-103 430.

H

220.5-221.5 431.

H

432.

H

367.9-368.5 433.

H

369.4-370.4 434.

H

294.2-296.7 435.

H

274-276 436.

H

299-301 437.

H

267-269 438.

H

439.

H

440.

H

441.

OH

442.

H

443.

H

444.

H

EXAMPLES G

R^(a) R^(b) R^(c) m_(p) 445.

H

446.

H

447.

H

448.

H

449.

H

450.

H

451.

H

208-209 452.

H

453.

H

454.

H

EXAMPLES H

m_(p) 455.

181-183 Decomp. 456.

272-274 Decomp. 457.

>315 458.

183-184

Ranges of Indications

It has been found that the compounds of formula 1 are characterised by avariety of possible applications in the therapeutic field. Particularmention should be made of those applications for which the compounds offormula 1 according to the invention are preferably used by virtue oftheir pharmaceutical activity as PI3-kinase modulators.

Generally speaking, these are diseases in whose pathology PI3-kinasesare implicated, particularly inflammatory and allergic diseases.Particular mention should be made of inflammatory and allergicrespiratory complaints, inflammatory diseases of the gastrointestinaltract, inflammatory diseases of the motor apparatus, inflammatory andallergic skin diseases, inflammatory eye diseases, diseases of the nasalmucosa, inflammatory or allergic ailments which involve autoimmunereactions or inflammation of the kidneys. The treatment may besymptomatic, adaptive, curative or preventative.

Respiratory complaints deserving special mention would be chronic and/orobstructive respiratory complaints. The compounds of formula 1 accordingto the invention may, by virtue of their pharmacological properties,bring about a reduction in

-   -   Tissue Damage    -   Inflammation of the airways    -   bronchial hyperreactivity    -   the process of reconstruction of the lung as a result of        inflammation    -   worsening of the disease (progression).

The compounds according to the invention are particularly preferred forpreparing a medicament for the treatment of chronic bronchitis, acutebronchitis, bronchitis caused by bacterial or viral infection or fungior helminths, allergic bronchitis, toxic bronchitis, chronic obstructivebronchitis (COPD), asthma (intrinsic or allergic), pediatric asthma,bronchiectasis, allergic alveolitis, allergic or non-allergic rhinitis,chronic sinusitis, cystic fibrosis or mucoviscidosis,alpha-1-antitrypsin deficiency, cough, pulmonary emphysema, interstitiallung diseases such as e.g. pulmonary fibrosis, asbestosis and silicosisand alveolitis; hyperreactive airways, nasal polyps, pulmonary oedemasuch as e.g. toxic pulmonary oedema and ARDS/IRDS, pneumonitis ofdifferent origins, e.g. radiation-induced or by caused by aspiration orinfectious pneumonitis, collagenoses such as lupus eryth, systemicsclerodermy, sarcoidosis or Boeck's disease.

The compounds of formula 1 are also suitable for the treatment ofdiseases of the skin, such as e.g. psoriasis, contact dermatitis, atopicdermatitis, alopecia areata (circular hair loss), erythema exsudativummultiforme (Stevens-Johnson Syndrome), dermatitis herpetiformis,sclerodermy, vitiligo, nettle rash (urticaria), lupus erythematodes,follicular and surface pyodermy, endogenous and exogenous acne, acnerosacea and other inflammatory or allergic or proliferative skindiseases.

Moreover, the compounds of formula 1 are suitable for therapeutic use incases of inflammatory or allergic complaints which involve autoimmunereactions, such as e.g. inflammatory bowel diseases, e.g. Crohn'sdisease or ulcerative colitis; diseases of the arthritis type, such ase.g. rheumatoid or psoriatic arthritis, osteoarthritis, rheumatoidspondylitis and other arthritic conditions or multiple sclerosis.

The following general inflammatory or allergic diseases may also bementioned, which can be treated with medicaments containing compounds offormula 1:

-   -   inflammation of the eye, such as e.g. conjunctivitis of various        kinds, e.g. caused by infections with fungi or bacteria,        allergic conjunctivitis, irritable conjunctivitis, drug-induced        conjunctivitis, keratitis, uveitis    -   diseases of the nasal mucosa, such as e.g. allergic        rhinitis/sinusitis or nasal polyps    -   inflammatory or allergic conditions, such as e.g. systemic lupus        erythematodes, chronic hepatitis, kidney inflammations such as        glomerulonephritis, interstitial nephritis or idiopathic        nephrotic syndrome.

Other diseases which may be treated with a drug containing compounds offormula 1 on the basis of their pharmacological activity include toxicor septic shock syndrome, atherosclerosis, middle ear infections (otitismedia), hypertrophy of the heart, cardiac insufficiency, stroke,ischaemic reperfusion injury or neurodegenerative diseases such asParkinson's disease or Alzheimer's.

Combinations

The compounds of formula 1 may be used on their own or in conjunctionwith other active substances of formula 1 according to the invention. Ifdesired the compounds of general formula 1 may also be used inconjunction with other pharmacologically active substances.

Preferably active substances are used which are selected, for example,from among the betamimetics, anticholinergics, corticosteroids,PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, dopamine-agonists,H1-antihistamines, PAF-antagonists and PI3-kinase inhibitors or doubleor triple combinations thereof, such as for example combinations of

-   -   Betamimetics with corticosteroids, PDE4-inhibitors,        EGFR-inhibitors or LTD4-antagonists,    -   Anticholinergics with betamimetics, corticosteroids,        PDE4-inhibitors, EGFR-inhibitors or LTD4-antagonists,    -   corticosteroids with PDE4-inhibitors, EGFR-inhibitors or        LTD4-antagonists    -   PDE4-inhibitors with EGFR-inhibitors or LTD4-antagonists    -   EGFR-inhibitors with LTD4-antagonists.

The invention also encompasses combinations of three active substances,each selected from one of the above-mentioned categories of compounds.

Suitable betamimetics used are preferably compounds selected from amongalbuterol, arformoterol, bambuterol, bitolterol, broxaterol, carbuterol,clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol,isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine,metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol,rimiterol, ritodrine, salmefamol, salmeterol, sulphsoterenol,sulphonterol, terbutaline, tiaramide, tolubuterol, zinterol, CHF-1035,HOKU-81, KUL-1248 and

-   3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzyl-sulphonamide-   5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one-   4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone-   1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol-   1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol-   1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol-   1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol-   1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol-   1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol-   5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one-   1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert-butylamino)ethanol-   6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one-   6-hydroxy-8-{1-hydroxy-2-[2-(ethyl    4-phenoxy-acetate)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one-   6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetic    acid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one-   8-{2-[1,1-dimethyl-2-(2,4,6-trimethyl    phenyl)-ethylamino]-1-hydroxy-ethyl}6-hydroxy-4H-benzo[1,4]oxazin-3-one-   6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one-   6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1,1dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one-   8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one-   8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one-   4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyric    acid-   8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one-   1-(4-ethoxy-carbonylamino-3-cyano-5-fluorophenyl)-2-(tert-butylamino)ethanol    optionally in the form of the racemates, enantiomers, diastereomers    and optionally in the form of the pharmacologically acceptable acid    addition salts, solvates or hydrates thereof. According to the    invention the acid addition salts of the betamimetics are preferably    selected from among the hydrochloride, hydrobromide, hydroiodide,    hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate,    hydromaleate, hydroacetate, hydrocitrate, hydrofumarate,    hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and    hydro-p-toluenesulphonate.

The anticholinergics used are preferably compounds selected from amongthe tiotropium salts, preferably the bromide salt, oxitropium salts,preferably the bromide salt, flutropium salts, preferably the bromidesalt, ipratropium salts, preferably the bromide salt, glycopyrroniumsalts, preferably the bromide salt, trospium salts, preferably thechloride salt, tolterodine. In the above-mentioned salts the cations arethe pharmacologically active ingredients. As anions the above-mentionedsalts may preferably contain chloride, bromide, iodide, sulphate,phosphate, methanesulphonate, nitrate, maleate, acetate, citrate,fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulphonate,while chloride, bromide, iodide, sulphate, methanesulphonate orp-toluenesulphonate are preferred as counter-ions. Of all the salts thechloride, bromide, iodide and methanesulphonate are particularlypreferred. Other named compounds are:

-   -   tropenol 2,2-diphenylpropionate-methobromide    -   scopine 2,2-diphenylpropionate-methobromide    -   scopine 2-fluoro-2,2-diphenylacetate-methobromide    -   tropenol 2-fluoro-2,2-diphenylacetate-methobromide    -   tropenol 3,3′,4,4′-tetrafluorobenzilate-methobromide    -   scopine 3,3′,4,4′-tetrafluorobenzilate-methobromide    -   tropenol 4,4′-difluorobenzylate-methobromide    -   scopine 4,4′-difluorobenzylate-methobromide    -   tropenol 3,3′-difluorobenzylate-methobromide    -   scopine 3,3′-difluorobenzylate-methobromide    -   tropenol 9-hydroxy-fluorene-9-carboxylate-methobromide    -   tropenol 9-fluoro-fluorene-9-carboxylate-methobromide    -   scopine 9-hydroxy-fluorene-9-carboxylate-methobromide    -   scopine 9-fluoro-fluorene-9-carboxylate-methobromide    -   tropenol 9-methyl-fluorene-9-carboxylate-methobromide    -   scopine 9-methyl-fluorene-9-carboxylate-methobromide    -   cyclopropyltropine benzylate-methobromide    -   cyclopropyltropine 2,2-diphenylpropionat-methobromide    -   cyclopropyltropine 9-hydroxy-xanthene-9-carboxylate-methobromide    -   cyclotropine 9-methyl-fluorene-9-carboxylate-methobromide    -   cyclotropine 9-methyl-xanthene-9-carboxylate-methobromide    -   cyclotropine 9-hydroxy-fluorene-9-carboxylate-methobromide    -   methyl cyclopropyltropine 4,4′-difluorobenzylate-methobromide    -   tropenol 9-hydroxy-xanthene-9-carboxylate-methobromide    -   scopine 9-hydroxy-xanthene-9-carboxylate-methobromide    -   tropenol 9-methyl-xanthene-9-carboxylate-methobromide    -   scopine 9-methyl-xanthene-9-carboxylate methobromide    -   tropenol 9-ethyl-xanthene-9-carboxylate-methobromide    -   tropenol 9-difluormethyl-xanthene-9-carboxylate-methobromide    -   scopine 9-hydroxymethyl-xanthene-9-carboxylate-methobromide

Corticosteroids used here are preferably compounds selected from amongprednisolone, prednisone, butixocortpropionate, flunisolide,beclomethasone, triamcinolone, budesonide, fluticasone, mometasone,ciclesonide, rofleponide, dexamethasone, betamethasone, deflazacort,RPR-106541, NS-126, ST-26 and

-   (S)-fluoromethyl    6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionate-   (S)-(2-oxo-tetrahydro-furan-3S-yl)    6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothionate,-   etiprednol-dichloroacetate    optionally in the form of the racemates, enantiomers or    diastereomers thereof and optionally in the form of the salts and    derivatives, solvates and/or hydrates thereof. Any reference to    steroids includes a reference to any salts or derivatives, hydrates    or solvates thereof which may exist. Examples of possible salts and    derivatives of the steroids may be: alkali metal salts, such as for    example sodium or potassium salts, sulfobenzoates, phosphates,    isonicotinates, acetates, propionates, dihydrogenphosphates,    palmitates, pivalates or furoates thereof.

PDE4 inhibitors which may be used are preferably compounds selected fromamong enprofyllin, theophyllin, roflumilast, ariflo (cilomilast),tofimilast, pumafentrin, lirimilast, arofyllin, atizoram, D-4418,Bay-198004, BY343, CP-325,366, D-4396 (Sch-351591), AWD-12-281(GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T-440, T-2585,V-11294A, CI-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370 and

-   N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide-   (−)_(p)-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide-   (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone-   3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N′-[N²-cyano-5-methyl-isothioureido]benzyl)-2-pyrrolidone-   cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic    acid]-   2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)cyclohexan-1-one-   cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol]-   (R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate-   (S)-(−)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate-   9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine-   9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine    optionally in the form of the racemates, enantiomers, diastereomers    and optionally in the form of the pharmacologically acceptable acid    addition salts, solvates or hydrates thereof. Preferably, according    to the invention, the acid addition salts of the PDE4 inhibitors are    selected from among the hydrochloride, hydrobromide, hydroiodide,    hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate,    hydromaleate, hydroacetate, hydrocitrate, hydrofumarate,    hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and    hydro-p-toluenesulphonate.

LTD4-antagonists which may be used are preferably compounds selectedfrom among montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523),MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707, L-733321 and

-   1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropane-acetic    acid,-   1-(((1(R)-3(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane-acetic    acid-   [2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic    acid    optionally in the form of the racemates, enantiomers, diastereomers    and optionally in the form of the pharmacologically acceptable acid    addition salts, solvates or hydrates thereof. Preferably, according    to the invention, the acid addition salts of the LTD4-antagonists    are selected from among the hydrochloride, hydrobromide,    hydroiodide, hydrosulphate, hydrophosphate, hydromethanesulphonate,    hydronitrate, hydromaleate, hydroacetate, hydrocitrate,    hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate,    hydrobenzoate und hydro-p-toluenesulphonate. By salts or derivatives    which the LTD4-antagonists may be capable of forming are meant, for    example: alkali metal salts, such as for example sodium or potassium    salts, alkaline earth metal salts, sulphobenzoates, phosphates,    isonicotinates, acetates, propionates, dihydrogenphosphates,    palmitates, pivalates or furoates.

EGFR-inhibitors which may be used are preferably compounds selected fromamong cetuximab, trastuzumab, ABX-EGF, Mab ICR-62 and

-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]-amino}-7-cyclopentyloxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinylcarbonyl)amino]-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine-   3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline-   4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulphonyl-ethyl)amino]methyl}-furan-2-yl)quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-[1-(tert-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N²-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline    optionally in the form of the racemates, enantiomers, diastereomers    and optionally in the form of the pharmacologically acceptable acid    addition salts, solvates or hydrates thereof. Preferably, according    to the invention, the acid addition salts of the EGFR-inhibitors are    selected from among the hydrochloride, hydrobromide, hydroiodide,    hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate,    hydromaleate, hydroacetate, hydrocitrate, hydrofumarate,    hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and    hydro-p-toluenesulphonate.

Dopamine agonists which may be used are preferably compounds selectedfrom among bromocriptin, cabergolin, alpha-dihydroergocryptin, lisuride,pergolide, pramipexol, roxindol, ropinirol, talipexol, terguride andviozan, optionally in the form of the racemates, enantiomers,diastereomers and optionally in the form of the pharmacologicallyacceptable acid addition salts, solvates or hydrates thereof.

Preferably, according to the invention, the acid addition salts of theDopamine agonists are selected from among the hydrochloride,hydrobromide, hydroiodide, hydrosulphate, hydrophosphate,hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate,hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.

H1-Antihistamines which may be used are preferably compounds selectedfrom among epinastin, cetirizin, azelastin, fexofenadin, levocabastin,loratadin, mizolastin, ketotifen, emedastin, dimetinden, clemastin,bamipin, cexchlorpheniramine, pheniramine, doxylamine, chlorphenoxamine,dimenhydrinate, diphenhydramine, promethazine, ebastin, desloratidineand meclozine, optionally in the form of the racemates, enantiomers,diastereomers and optionally in the form of the pharmacologicallyacceptable acid addition salts, solvates or hydrates thereof.Preferably, according to the invention, the acid addition salts of theH1-Antihistamines are selected from among the hydrochloride,hydrobromide, hydroiodide, hydrosulphate, hydrophosphate,hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate,hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.

PAF-Antagonists which may be used are preferably compounds selected fromamong

-   4-(2-chlorophenyl)-9-methyl-2-[3(4-morpholinyl)-3-propanon-1-yl]-6H-thieno-[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepine-   6-(2-chlorophenyl)-8,9-dihydro-1-methyl-8-[(4-morpholinyl)carbonyl]-4H,7H-cyclo-penta-[4,5]thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine    optionally in the form of the racemates, enantiomers, diastereomers    and optionally in the form of the pharmacologically acceptable acid    addition salts, solvates or hydrates thereof. Preferably, according    to the invention, the acid addition salts of the PAF-Antagonists are    selected from among the hydrochloride, hydrobromide, hydroiodide,    hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate,    hydromaleate, hydroacetate, hydrocitrate, hydrofumarate,    hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and    hydro-p-toluenesulphonate.

Formulations

The compounds according to the invention may be administered by oral,transdermal, inhalative, parenteral or sublingual route. The compoundsaccording to the invention are present as active ingredients inconventional preparations, for example in compositions consistingessentially of an inert pharmaceutical carrier and an effective dose ofthe active substance, such as for example tablets, coated tablets,capsules, lozenges, powders, solutions, suspensions, emulsions, syrups,suppositories, transdermal systems etc. An effective dose of thecompounds according to the invention is between 0.1 and 5000, preferablybetween 1 and 500, more preferably between 5-300 mg/dose for oraladministration, and between 0.001 and 50, preferably between 0.1 and 10mg/dose for intravenous. subcutaneous or intramuscular administration.For inhalation, according to the invention, solutions containing 0.01 to1.0, preferably 0.1 to 0.5% active substance are suitable. Foradministration by inhalation the use of powders, ethanolic or aqueoussolutions is preferred. It is also possible to use the compoundsaccording to the invention as a solution for infusion, preferably in aphysiological saline or nutrient saline solution.

The compounds according to the invention may be used on their own or inconjunction with other active substances according to the invention,optionally also in conjunction with other pharmacologically activesubstances. Suitable formulations include, for example, tablets,capsules, suppositories, solutions, syrups, emulsions or dispersiblepowders. Corresponding tablets may be obtained for example by mixing theactive substance(s) with known excipients, for example inert diluents,such as calcium carbonate, calcium phosphate or lactose, disintegrantssuch as maize starch or alginic acid, binders such as starch orgelatine, lubricants such as magnesium stearate or talc and/or agentsfor delaying release, such as carboxymethyl cellulose, cellulose acetatephthalate, or polyvinyl acetate. The tablets may also comprise severallayers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups containing the active substances or combinations thereofaccording to the invention may additionally contain a sweetener such assaccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. aflavouring such as vanillin or orange extract. They may also containsuspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Solutions for injection are prepared in the usual way, e.g. with theaddition of preservatives such as p-hydroxybenzoates, or stabiliserssuch as alkali metal salts of ethylenediamine tetraacetic acid, andtransferred into injection vials or ampoules.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules. Suitable suppositories may be made forexample by mixing with carriers provided for this purpose, such asneutral fats or polyethyleneglycol or the derivatives thereof.

A therapeutically effective daily dose is between 1 and 2000 mg,preferably 10-500 mg per adult.

The Examples which follow illustrate the present invention withoutrestricting its scope:

Examples of Pharmaceutical Formulations

A) Tablets per tablet active substance 100 mg lactose 140 mg maizestarch 240 mg polyvinylpyrrolidone  15 mg magnesium stearate  5 mg 500mg

The finely ground active substance, lactose and some of the corn starchare mixed together. The mixture is screened, then moistened with asolution of polyvinylpyrrolidone in water, kneaded, granulated while wetand dried. The granulate, the rest of the corn starch and the magnesiumstearate are screened and mixed together. The mixture is compressed toform tablets of a suitable shape and size.

B) Tablets per tablet active substance 80 mg corn starch 190 mg  lactose55 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mgsodium-carboxymethyl starch 23 mg magnesium stearate  2 mg 400 mg 

The finely ground active substance, some of the corn starch, lactose,microcrystalline cellulose and polyvinylpyrrolidone are mixed together,the mixture is screened and worked with the remaining corn starch andwater to form a granulate which is dried and screened. Thesodium-carboxymethyl starch and the magnesium stearate are added andmixed in and the mixture is compressed to form tablets of a suitablesize.

C) Coated tablets per coated tablet Active substance  5 mg Corn starch41.5 mg   Lactose 30 mg Polyvinylpyrrolidone  3 mg Magnesium stearate0.5 mg  80 mg

The active substance, corn starch, lactose and polyvinylpyrrolidone arethoroughly mixed and moistened with water. The moist mass is pushedthrough a screen with a 1 mm mesh size, dried at about 45° C. and thegranules are then passed through the same screen. After the magnesiumstearate has been mixed in, convex tablet cores with a diameter of 6 mmare compressed in a tablet-making machine. The tablet cores thusproduced are coated in a known manner with a covering consistingessentially of sugar and talc. The finished coated tablets are polishedwith wax

D) Capsules per capsule Active substance   50 mg Corn starch 268.5 mgMagnesium stearate  1.5 mg   320 mg

The substance and corn starch are mixed and moistened with water. Themoist mass is screened and dried. The dry granules are screened andmixed with magnesium stearate. The finished mixture is packed into size1 hard gelatine capsules.

E) Ampoule solution active substance 50 mg sodium chloride 50 mg waterfor inj. 5 ml

The active substance is dissolved in water at its own pH or optionallyat pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. Thesolution obtained is filtered free from pyrogens and the filtrate istransferred under aseptic conditions into ampoules which are thensterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50mg of active substance.

F) Suppositories Active substance  50 mg Solid fat 1650 mg 1700 mg

The hard fat is melted. At 40° C. the ground active substance ishomogeneously dispersed. It is cooled to 38° C. and poured into slightlychilled suppository moulds.

G) Oral suspension active substance 50 mg hydroxyethylcellulose 50 mgsorbic acid 5 mg sorbitol (70%) 600 mg glycerol 200 mg flavouring 15 mgwater ad 5 ml

Distilled water is heated to 70° C. Hydroxyethyl-cellulose is dissolvedtherein with stirring. After the addition of sorbitol solution andglycerol the mixture is cooled to ambient temperature. At ambienttemperature, sorbic acid, flavouring and substance are added. Toeliminate air from the suspension it is evacuated with stirring.

1. A compound of formula 1;

with the proviso that the circular line designated A denotes an aromaticsystem; wherein Y denotes carbon, nitrogen atom, sulphur; Z denotescarbon, nitrogen atom, sulphur; j denotes 1, 2 or 3; k denotes 0 or 1;R^(a) denotes H, COR⁸, NR⁹R¹⁰, NO₂, OR⁸, SR¹¹, SOR¹¹, SO₂R¹¹,NHCO—C₁₋₆-alkyl-NH₂, or a group selected from among C₁₋₆-alkyl,C₂₋₆-alkenyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkenyl, C₁₋₆-haloalkyl, aryl,C₇₋₁₁-aralkyl, spiro, het, hetaryl and CH₂—O-aryl, which may optionallybe substituted; R⁸ denotes C₁₋₆-alkyl, C₃₋₆-cycloalkyl, NH₂, hetaryl oraryl, optionally substituted by one or more halogens or C₁₋₄-alkyl; R⁹denotes H, COOR¹², CONR¹² or C₁₋₆-alkyl, optionally substituted by oneor more COOH, N(C₁₋₆-alkyl)₂ or het, optionally substituted by one ormore C₁₋₆-alkyl; or R⁹ denotes het, optionally substituted by one ormore C₁₋₄-alkyl; R¹⁰ denotes H, C₁₋₆-alkyl, CO—C₁₋₆-alkyl orC₂₋₆-alkynyl; R¹¹ denotes C₁₋₆-alkyl, optionally substituted by one ormore N(C₁₋₄-alkyl)₂; R^(b) denotes R⁴, OR⁴, —CH₂OR⁴, COR⁴, COOR⁴,CONR⁴R⁵, NR⁴R⁵, NR⁵COR⁴, NR⁵COOR⁴, NR⁵CONR⁴R⁵, NR⁵SOR⁴ or NR⁵SO₂R⁴; R⁴,R⁵ denote H, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkylene-OH, C₂₋₆-alkenyl,C₇₋₁₁-aralkyl, C₂₋₄-alkenyl-aryl, C₂₋₄-alkynyl-aryl, C₁₋₄-alkyl-hetaryl,C₂₋₄-alkenyl-hetaryl, C₂₋₄-alkynyl-hetaryl, C₂₋₆-alkynyl, optionallysubstituted by Si(C₁₋₄-alkyl)₃, or R⁴ denotes a group selected fromamong aryl, het, hetaryl and optionally substituted by C₁₋₄-alkyl; or R⁴and R⁵ together form a five-, six- or seven-membered ring consisting ofcarbon atoms and optionally a heteroatom selected from among oxygen,nitrogen and sulphur; R^(c) denotes NHR⁶ or a group selected from among

wherein B denotes a bond, C₁₋₆-alkyl, C₂₋₆-alkenyl or C₂₋₆-alkynyl; R⁶denotes H or a group selected from among C₁₋₄-alkyl, C₂₋₄-alkenyl,C₂₋₄-alkynyl, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkenyl, het, aryl, hetaryloptionally substituted by one or more groups R^(6.1); R^(6.1) denoteshalogen, CF₃, OH, CN, OMe, SO₂(C₁₋₄-alkyl); R⁷ denotes H, C₁₋₄-alkyl,C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₃₋₆-cycloalkyl, NR^(7.1)R^(7.2), OR^(7.2),SR^(7.2), hetaryl, het, optionally substituted by C₁₋₄-alkyl or CONH₂;R^(7.1) denotes H, C₁₋₆-alkyl, (CH₂)₂₋₄R^(7.1.1) or COObutyl; R^(7.2)denotes H, C₁₋₆-alkyl, optionally substituted by one or more OH;R^(7.1.1) denotes NR^(7.1.1.1)R^(7.1.1.2), het or 1-imidazolyl,2-(N-ethylpyrrolidine); R^(7.1.1.1) denotes H or C₁₋₆-alkyl; R^(7.1.1.2)denotes H or C₁₋₆-alkyl; or a pharmacologically acceptable salt thereof,with the proviso that R^(a) cannot be H or Me if Y is nitrogen; Z isnitrogen; j is 2; k is 0; R^(b) is H and R^(c) is NHCONH-Et.
 2. Thecompound of formula 1 according to claim 1; wherein R^(a) denotes agroup selected from among aryl, C₇₋₁₁-aralkyl and hetaryl, which mayoptionally be substituted by one or more groups selected from among R¹,R² and R³; R¹ and R² independently of one another denote C₁₋₆-alkyl,C₂₋₆-alkenyl C₂₋₆-alkynyl, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkenyl,C₁₋₆-haloalkyl, C₁₋₆-alkylene-COOH, C₁₋₆-alkoxy, halogen, OH, CN,COR^(1.1), O—C₁₋₄-haloalkyl, NO₂ or SR^(1.1), SOR^(1.1), SO₂R^(1.1), hetor hetaryl, R^(1.1) denotes OH, C₁₋₆-alkyl, C₂₋₆-alkenyl C₂₋₆-alkynyl,NR^(1.1.1)R^(1.1.2) R^(1.1.1) denotes H, C₁₋₆-alkyl, optionallysubstituted by a group selected from among NH₂, NHMe, NMe₂; R^(1.1.2)denotes H, C₁₋₆-alkyl; or R^(1.1.1) and R^(1.1.2) together form a five-or six-membered heterocyclic ring, which may optionally be substitutedby a group selected from among methyl, ethyl, propyl; R³ denotes a groupselected from among

wherein X denotes a bond or C₁₋₄-alkylene; X′ denotes C₁₋₄-alkylene,C₂₋₄-alkenylene or C₁₋₄-alkynylene R^(3a) denotes a group, which may beidentical or different, selected from among R^(3.1), R^(3.2) andR^(3.3); R^(3.1) denotes spiro or het, while het may optionally besubstituted by one or more R^(3.1.1); R^(3.1.1) denotes C₁₋₆-alkyl,C₂₋₆-alkenyl, OH, C₁₋₄-alkylene-OH,C₁₋₄-alkylene-NR^(3.1.1.1)R^(3.1.1.2), COR^(3.1.1.1), COOR^(3.1.1.1),CONR^(3.1.1.1)R^(3.1.1.2), NR^(3.1.1.2), R^(3.1.1.2), het, hetaryl,NHCOR^(3.1.1.1) R^(3.1.1.1) denotes a group selected from among H,C₁₋₄-alkyl, aryl and C₇₋₁₁-aralkyl; optionally substituted by a groupselected from among halogen, OH and CN; R^(3.1.1.2) denotes H,C₁₋₄-alkyl; R^(3.2) denotes a group selected from among C₃₋₆-cycloalkyl,het, hetaryl and spiro which is optionally substituted by one or moreR^(3.2.1) R^(3.2.1) denotes C₁₋₆-alkyl, C₃₋₆-cycloalkyl, OH,NR^(3.2.1.1)R^(3.2.1.2), NHCOR^(3.2.1.3) or het, optionally substitutedby one or more groups selected from among C₁₋₄-alkyl, SO₂R^(3.2.1.1),CH₂—C₃₋₆-cycloalkyl and aryl; R^(3.2.1.1) denotes H, C₁₋₄-alkyl orC₇₋₁₁- aralkyl; R^(3.2.1.2) denotes H, C₁₋₄-alkyl or C₇₋₁₁- aralkyl;R^(3.2.1.3) denotes aryl, C₇₋₁₁-aralkyl; or C₁₋₆-alkyl, which isoptionally substituted by one or two R^(3.2.2); R^(3.2.2) denotesC₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, COOR^(3.2.2.1)CONR^(3.2.2.1)R^(3.2.2.2), NR^(3.2.2.1)R^(3.2.2.2), NHCOR^(3.2.2.1),C₁₋₆-haloalkyl, CN, OR^(3.2.2.1), SO₂R^(3.2.2.1), C₃₋₆-cycloalkyl,CO-het, C₂₋₄-alkynyl-hetaryl, guanidine or a group selected from amonghet, hetaryl and aryl, which is optionally substituted by one or moregroups selected from among halogen, C₁₋₆-alkyl,CONR^(3.2.2.1)R^(3.2.2.2), OH, imidazolidinone; R^(3.2.2.1) denotes H orC₁₋₆-alkyl, aryl, C₇₋₁₁-aralkyl R^(3.2.2.2) denotes H or C₁₋₆-alkyl; oraryl, which is optionally substituted by one or two R^(3.2.3) R^(3.2.3)denotes a group selected from among NH—C₁₋₆-alkyl-N(C₁₋₆-alkyl)₂ or het,while het may optionally be substituted by a C₁₋₆-alkyl group; R^(3.3)denotes H or a group selected from among C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₁₋₆-haloalkyl and aryl, which may optionally besubstituted by one or more groups R^(3.3.1); R^(3.3.1) denotesC₃₋₆-cycloalkyl, C₃₋₆-cycloalkenyl, OR^(3.3.1.1),NR^(3.3.1.1)R^(3.3.1.2), CONR^(3.3.1.1)R^(3.3.1.2), COOR^(3.3.1.1),NR^(3.3.1.1)COR^(3.3.1.2), SOR^(3.3.1.1), SO₂R^(3.3.1.1),C(NR^(3.3.1.1)R^(3.3.1.2))NR^(3.3.1.3),NR^(3.3.1.1)CONR^(3.3.1.2)R^(3.3.1.3), OH, CN, halogen or het,optionally substituted by one or more groups selected from amongC₁₋₄-alkyl, SO₂R^(3.2.1.1), SO₂C₁₋₄-alkyl, SO₂C₇₋₁₁-aralkyl,CH₂—C₃₋₆-cycloalkyl and aryl; R^(3.3.1.1), R^(3.3.1.2) and R^(3.3.1.3)denote a group selected from among C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₇₋₁₁-aralkyl, C₂₋₄-alkenyl-aryl, C₂₋₄-alkynyl-aryl,C₁₋₄-alkyl-hetaryl, C₂₋₄-alkenyl-hetaryl, C₂₋₄-alkynyl-hetaryl,COC₁₋₄-alkyl-hetaryl, COC₂₋₄-alkenyl-hetaryl, COC₂₋₄-alkynyl-hetaryl; ortwo of the groups R^(3.3.1.1), R^(3.3.1.2) and R^(3.3.1.3) together forma ring, consisting of carbon atoms and optionally a heteroatom selectedfrom among oxygen, nitrogen and sulphur; R^(a) denotes H, C₁₋₆-alkyl,C₂₋₆-alkenyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkenyl, C₁₋₆-haloalkyl, COR⁸,NR⁹R¹⁰, NO₂, OR⁸, SR¹¹, SOR¹¹, SO₂R¹¹, NHCO—C₁₋₆-alkyl-NH₂, spiro or agroup selected from among C₇₋₁₁- aralkyl, CH₂—O-aryl and het which mayoptionally be substituted by one or more halogens, C₁₋₆-alkyl,CO—C₁₋₄-haloalkyl, C₁₋₄-alkyl-NH₂ or CH₂NHCOOR¹²; R⁸ denotes C₁₋₆-alkyl,C₃₋₆-cycloalkyl, NH₂, hetaryl or aryl, optionally substituted by one ormore halogens or C₁₋₄-alkyl; R⁹ denotes H, COOR¹², CONR¹² or C₁₋₆-alkyl,optionally substituted by one or more COOH, N(C₁₋₆-alkyl)₂ or het,optionally substituted by one or more C₁₋₆-alkyl; or R⁹ denotes het,optionally substituted by one or more C₁₋₄-alkyl; R¹⁰ denotes H,C₁₋₆-alkyl, CO—C₁₋₆-alkyl or C₂₋₆-alkynyl; R¹¹ denotes C₁₋₆-alkyl,optionally substituted by one or more N(C₁₋₄-alkyl)₂; R¹² denotes H,C₁₋₆-alkyl; or a pharmacologically acceptable salt thereof.
 3. Thecompound of formula 1 according to claim 1; wherein R^(a) denotes agroup selected from among aryl, C₇₋₁₁-aralkyl and hetaryl, which mayoptionally be substituted by one or more groups selected from among R¹,R² and R³; R¹ and R² independently of one another denote C₁₋₆-alkyl,C₂₋₆-alkenyl C₂₋₆-alkynyl, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkenyl,C₁₋₆-haloalkyl, C₁₋₆-alkylene-COOH, C₁₋₆-alkoxy, halogen, OH, CN,COR^(1.1), O—C₁₋₄-haloalkyl, NO₂ or SR^(1.1), SOR^(1.1), SO₂R^(1.1), hetor hetaryl, R^(1.1) denotes OH, C₁₋₆-alkyl, C₂₋₆-alkenyl C₂₋₆-alkynyl,NR^(1.1.1)R^(1.1.2) R^(1.1.1) denotes H, C₁₋₆-alkyl, optionallysubstituted by a group selected from among NH₂, NHMe, NMe₂; R^(1.1.2)denotes H, C₁₋₆-alkyl; or R^(1.1.1) and R^(1.1.2) together form a five-or six-membered heterocyclic ring, which may optionally be substitutedby a group selected from among methyl, ethyl, propyl; R³ denotes a groupselected from among

wherein X denotes a bond or C₁₋₄-alkylene; R^(3a) denotes a group, whichmay be identical or different, selected from among R^(3.1), R^(3.2) andR^(3.3) R^(3.1) denotes spiro or het, while het may optionally besubstituted by one or more R^(3.11) R^(3.1.1) denotes C₁₋₆-alkyl,C₂₋₆-alkenyl, OH, C₁₋₄-alkylene-OH,C₁₋₄-alkylene-NR^(3.1.1.1)R^(3.1.1.2), COR^(3.1.1.1), COOR^(3.1.1.1),CONR^(3.1.1.1)R^(3.1.1.2), NR^(3.1.1.1)R^(3.1.1.2), het, hetaryl,NHCOR^(3.1.1.1) R^(3.1.1.1) denotes a group selected from among H,C₁₋₄-alkyl, aryl and C₇₋₁₁-aralkyl; optionally substituted by a groupselected from among halogen, OH and CN; R^(3.1.1.2) denotes H,C₁₋₄-alkyl; R^(3.2) denotes a group selected from among C₃₋₆-cycloalkyl,het, hetaryl and spiro which is optionally substituted by one or moreR^(3.2.1) R^(3.2.1) denotes C₁₋₆-alkyl, C₃₋₆-cycloalkyl, OH,—NR^(3.2.1.1)R^(3.2.1.2) NHCOR^(3.2.1.3) or het, optionally substitutedby one or more groups selected from among C₁₋₄-alkyl, SO₂R^(3.2.1.1),CH₂—C₃₋₆-cycloalkyl and aryl; R^(3.2.1.1) denotes H, C₁₋₄-alkyl orC₇₋₁₁- aralkyl; R^(3.2.1.2) denotes H, C₁₋₄-alkyl or C₇₋₁₁- aralkyl;R^(3.2.1.3) denotes aryl, C₇₋₁₁-aralkyl; or —C₁₋₆-alkyl, which isoptionally substituted by one or two R^(3.2.1.2) R^(3.2.2) denotesC₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, COOR^(3.2.2.1),CONR^(3.2.2.1)R^(3.2.2.2), NR^(3.2.2.1)R^(3.2.2.2), NHCOR^(3.2.2.1),C₁₋₆-haloalkyl, CN, OR^(3.2.2.1), SO₂R^(3.2.2.1), C₃₋₆-cycloalkyl,CO-het, C₂₋₄-alkynyl-hetaryl, guanidine or a group selected from amonghet, hetaryl and aryl, which is optionally substituted by one or moregroups selected from among halogen, C₁₋₆-alkyl,CONR^(3.2.2.1)R^(3.2.2.2), OH, imidazolidinone; R^(3.2.2.1) denotes H orC₁₋₆-alkyl, aryl, C₇₋₁₁-aralkyl R^(3.2.2.2) denotes H or C₁₋₆-alkyl; oraryl, which is optionally substituted by one or two R^(3.2.3) R^(3.2.3)denotes a group selected from among NH—C₁₋₆-alkyl-N(C₁₋₆-alkyl)₂ or het,while het may optionally be substituted by a C₁₋₆-alkyl group; R^(3.3)denotes H or a group selected from among C₁₋₆-alkyl, C₂₋₄-alkenyl,C₂₋₄-alkynyl, C₁₋₄-haloalkyl and aryl, which may optionally besubstituted by one or more groups R^(3.3.1); R^(3.3.1) denotesC₅₋₆-cycloalkyl, C₅₋₆-cycloalkenyl, OR^(3.3.1.1),NR^(3.3.1.1)R^(3.3.1.2), CONR^(3.3.1.1)R^(3.3.1.2), COOR^(3.3.1.1),NR^(3.3.1.1)COR^(3.3.1.2), SOR^(3.3.1.1), SO₂R^(3.3.1.1),C(NR^(3.3.1.1)R^(3.3.1.2))NR^(3.3.1.3),NR^(3.3.1.1)CONR^(3.3.1.2)R^(3.3.1.3), OH, CN, halogen or het,optionally substituted by one or more groups selected from amongC₁₋₄-alkyl, SO₂R^(3.2.1.1), SO₂C₁₋₄-alkyl, SO₂C₇₋₁₁- aralkyl,CH₂—C₃₋₆-cycloalkyl and aryl; R^(3.3.1.1), R^(3.3.1.2) and R^(3.3.1.3)denote a group selected from among C₁₋₄-alkyl, C₂₋₄-alkenyl,C₂₋₄-alkynyl, C₇₋₁₁-aralkyl, C₂₋₄-alkenyl-aryl, C₂₋₄-alkynyl-aryl,C₁₋₄-alkyl-hetaryl, C₂₋₄-alkenyl-hetaryl, C₂₋₄-alkynyl-hetaryl,COC₁₋₄-alkyl-hetaryl, COC₂₋₄-alkenyl-hetaryl, COC₂₋₄-alkynyl-hetaryl; ortwo of the groups R^(3.3.1.1), R^(3.3.1.2) and R^(3.3.1.3) together forma five-, six- or seven-membered ring, consisting of carbon atoms andoptionally a heteroatom selected from among oxygen, nitrogen andsulphur; R^(a) denotes H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₃₋₈-cycloalkyl,C₃₋₈-cycloalkenyl, C₁₋₆-haloalkyl, COR⁸, NR⁹R¹⁰, NO₂, OR⁸, SR¹¹, SOR¹¹,SO₂R¹¹, NHCO—C₁₋₆-alkyl-NH₂, spiro or a group selected from among C₇₋₁₁-aralkyl, CH₂—O-aryl and het which may optionally be substituted by oneor more halogens, C₁₋₆-alkyl, CO—C₁₋₄-haloalkyl, C₁₋₄-alkyl-NH₂ orCH₂NHCOOR¹²; R⁸ denotes C₁₋₆-alkyl, C₃₋₆-cycloalkyl, NH₂, hetaryl oraryl, optionally substituted by one or more halogens or C₁₋₄-alkyl; R⁹denotes H, COOR¹² or C₁₋₄-alkyl, optionally substituted by one or moreCOOH, N(C₁₋₄-alkyl)₂ or het, optionally substituted by one or moreC₁₋₄-alkyl; or R⁹ denotes het, optionally substituted by one or moreC₁₋₄-alkyl; R¹⁰ denotes H, C₁₋₆-alkyl, CO—C₁₋₄-alkyl or C₂₋₆-alkynyl;R¹¹ denotes C₁₋₆-alkyl, optionally substituted by one or moreN(C₁₋₄-alkyl)₂; R¹² denotes C₁₋₆-alkyl; R^(b) denotes R⁴, OR⁴, —CH₂OR⁴,COR⁴, COOR⁴, CONR⁴R⁵, NR⁴R⁵, NR⁵COR⁴, NR⁵COOR⁴, NR⁵CONR⁴R⁵, NR⁵SOR⁴ orNR⁵SO₂R⁴; R⁴ denotes H, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkylene-OH,C₂₋₆-alkenyl, C₇₋₁₁-aralkyl, C₂₋₄-alkenyl-aryl, C₂₋₄-alkynyl-aryl,C₁₋₄-alkyl-hetaryl, C₂₋₄-alkenyl-hetaryl, C₂₋₄-alkynyl-hetaryl,C₂₋₆-alkynyl, optionally substituted by Si(C₁₋₄-alkyl)₃, or R⁴ denotes agroup selected from among aryl, het, hetaryl and optionally substitutedby C₁₋₄-alkyl; R⁵ denotes H or C₁₋₆-alkyl; or R⁴ and R⁵ together form afive-, six- or seven-membered ring consisting of carbon atoms andoptionally a heteroatom selected from among oxygen, nitrogen andsulphur; R^(c) denotes NHR⁶ or a group selected from among

wherein B denotes a bond, C₁₋₄-alkyl or C₂₋₄-alkynyl; R⁶ denotes H or agroup selected from among C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl,C₃₋₆-cycloalkyl, C₃₋₆-cycloalkenyl, het, aryl, hetaryl optionallysubstituted by one or more groups R^(6.1;) R^(6.1) denotes halogen, CF₃,OH, CN, OMe, SO₂(C₁₋₄-alkyl); R⁷ denotes H, C₁₋₄-alkyl, C₂₋₄-alkenyl,C₂₋₄-alkynyl, C₃₋₆-cycloalkyl, NR^(7.1)R^(7.2), OR^(7.2), SR^(7.2),hetaryl, het, optionally substituted by C₁₋₄-alkyl or CONH₂; R^(7.1)denotes H, C₁₋₄-alkyl, (CH₂)₂₋₄R^(7.1.1) or COObutyl; R^(7.2) denotes H,C₁₋₆-alkyl, optionally substituted by one or more OH; R^(7.1.1) denotesNR^(7.1.1.1)R^(7.1.1.2), het or 1-imidazolyl, 2-(N-ethylpyrrolidine);R^(7.1.1.1) denotes H or C₁₋₆-alkyl; R^(7.1.1.2) denotes H orC₁₋₆-alkyl; or the pharmacologically acceptable salt thereof.
 4. Thecompound of formula 1 according to claim 1; wherein R^(a) denotes agroup selected from among aryl and C₇₋₁₁-aralkyl, which may optionallybe substituted by one or more groups selected from among R¹, R² and R³;or hetaryl optionally substituted by one or more C₁₋₄-alkyl; R¹ denotesC₁₋₄-alkyl, C₁₋₄-haloalkyl, C₁₋₄-alkylene-COOH, C₁₋₄-alkoxy, halogen,OH, CN, COR^(1.1), O—C₁₋₄-haloalkyl, NO₂ or SO₂R^(1.1); R^(1.1) denotesOH, methyl, NH₂, NHMe, NMe₂,

R² denotes C₁₋₄-alkyl, C₁₋₄-alkoxy or halogen; R³ denotes a groupselected from among

wherein n denotes 0 or 1; m denotes 0 or 1; o denotes 2; R^(3.1) denotesspiro or het, while het may optionally be substituted by one or moreR^(3.1.1); R^(3.1.1) denotes C₁₋₄-alkyl, C₂₋₄-alkenyl, OH,C₁₋₄-alkylene-OH, CH₂NEt₂, COMe, COOH, CONH₂, NH₂, het, hetaryl,

R^(3.2) denotes a group selected from among C₃₋₆-cycloalkyl, het,hetaryl and spiro which is optionally substituted by one or twoR^(3.2.1) R^(3.2.1) denotes C₁₋₄-alkyl, cyclopentyl, OH,—NR^(3.2.1.1)R^(3.2.1.2) or

or het, is optionally substituted by one or more groups selected fromamong methyl, SO₂R^(3.2.1.1),

R^(3.2.1.1) denotes H, methyl or benzyl; R^(3.2.1.2) denotes H, methylor benzyl; or —C₁₋₆-alkyl, which is optionally substituted by one or twoR^(3.2.2); R^(3.2.2) denotes C₂₋₄-alkenyl, C₂₋₄-alkynyl, COOR^(3.2.2.1),CONR^(3.2.2.1)R^(3.2.2.2), NR^(3.2.2.1)R^(3.2.2.2), NHCOR^(3.2.2.1),C₁₋₄-haloalkyl, CN, OH, SO₂R^(3.2.2.1), C₃₋₆-cycloalkyl or a groupselected from among

or a group selected from among het, hetaryl and aryl, which isoptionally substituted by one or more groups selected from among Cl,methyl, CONR^(3.2.2.1)R^(3.2.2.2), OH; R^(3.2.2.1) denotes H or methyl;R^(3.2.2.2) denotes H or methyl; or aryl, which is optionallysubstituted by one or two R^(3.2.3) R^(3.2.3) denotes a group selectedfrom among

R^(3.3) denotes H or a group selected from among C₁₋₆-alkyl and aryl,which may optionally be substituted by one or more groups R^(3.3.1);R^(3.3.1) denotes C₅₋₆-cycloalkyl, C₅₋₆-cycloalkenyl, OR^(3.3.1.1),NR^(3.3.1.1)R^(3.3.1.2)CONR^(3.3.1.1)R^(3.3.1.2), COOR^(3.3.1.1),NR^(3.3.1.1)COR^(3.3.1.2), SOR^(3.3.1.1), SO₂R^(3.3.1.1),C(NR^(3.3.1.1)R^(3.3.1.2))NR^(3.3.1.3),NR^(3.3.1.1)CONR^(3.3.1.2)R^(3.3.1.3), OH, CN, halogen or het,optionally substituted by one or more groups selected from amongC₁₋₄-alkyl, SO₂R^(3.2.1.1), SO₂C₁₋₄-alkyl, SO₂C₇₋₁₁- aralkyl,

R^(3.3.1.1), R^(3.3.1.2) and R^(3.3.1.3) denote a group selected fromamong C₁₋₄-alkyl, C₇₋₁₁-aralkyl, C₁₋₄-alkyl-hetaryl,COC₁₋₄-alkyl-hetaryl; R^(a) denotes H, C₁₋₆-alkyl, C₂₋₆-alkenyl,C₃₋₆-cycloalkyl, CF₃, COR⁸, NR⁹R¹⁰, NO₂, S(O)_(n)R¹¹, or a groupselected from among

or a group selected from among

which may optionally be substituted by one or more Cl; or a groupselected from among

which may optionally be substituted by one or more CH₃, COCF₃, CH₂NH₂ orCH₂NHCOOR¹²; R⁸ denotes C₁₋₄-alkyl, C₃₋₆-cycloalkyl, NH₂, furanyl orphenyl, optionally substituted by one or more chlorine; R⁹ denotes H,COOR¹² or piperidino, optionally substituted by one or more CH₃, or agroup selected from among C₁₋₄-alkyl, which may optionally besubstituted by one or more COOH, NMe₂ or 4-methylpiperazine; R¹⁰ denotesH, C₁₋₄-alkyl, C₂₋₄-alkynyl or COCH₃; R¹¹ denotes C₁₋₄-alkyl, optionallysubstituted by one or more NMe₂, R¹² denotes C₁₋₄-alkyl; R^(b) denotesR⁴, CH₂OR⁴, COR⁴, COOR⁴, CONR⁴R⁵, NH₂, NHCOOR⁴, NHCONR⁴R⁵ or OH; R⁴denotes H, C₁₋₄-alkyl, C₁₋₄-alkylene-OH, C₂₋₄-alkynyl, C₁₋₆-haloalkyl,aryl, het, hetaryl,

R⁵ denotes H or C₁₋₄-alkyl; R^(c) denotes NHR⁶ or a group selected fromamong

wherein B denotes a bond, C₁₋₄-alkyl or C₂₋₄-alkynyl; R⁶ denotes H,C₁₋₄-alkyl, C₃₋₆-cycloalkyl, C₇₋₁₁- aralkyl, aryl, optionallysubstituted by SO₂CH₃; R⁷ denotes H, NR^(7.1)R^(7.2), OR^(7.2),SR^(7.2), hetaryl, het, optionally substituted by C₁₋₄-alkyl or CONH₂,or a group selected from among

R^(7.1) denotes H, C₁₋₄-alkyl, (CH₂)₂R^(7.1.1) or COObutyl; R^(7.2)denotes H, C₁₋₄-alkyl; R^(7.1.1) denotes NR^(7.1.1.1)R^(7.1.1.2), het or1-imidazolyl, 2-(N-ethylpyrrolidine); R^(7.1.1.1) denotes H orC₁₋₆-alkyl; R^(7.1.1.2) denotes H or C₁₋₆-alkyl; or thepharmacologically acceptable salt thereof.
 5. The compound of formula 1according to claim 1; wherein R^(a) denotes phenyl or benzyl, in eachcase optionally substituted by one or more groups selected from amongR¹, R² and R³; or

R¹ denotes methyl, ethyl, propyl, butyl, CF₃, CH₂COOH, methoxy, F, Cl,Br, OH, CN, COR^(1.1), OCF₃, NO₂ or SO₂R^(1.1); R^(1.1) denotes OH,methyl, NH₂, NHMe, NMe₂,

R² denotes methyl, methoxy, F, Cl or Br; R³ denotes a group selectedfrom among

wherein n denotes 0 or 1; m denotes 0 or 1; o denotes 2; R^(3.1) denotesa group selected from among

or a group selected from among

which may optionally be substituted by one or more R^(3.1.1); R^(3.1.1)denotes methyl, ethyl, OH, CH₂OH, CH₂CH₂OH, CH₂NEt₂, COMe, COOH, CONH₂,NH₂,

R^(3.2) denotes a group selected from among

which is optionally substituted by one or more groups selected fromamong methyl, ethyl, cyclopentyl, OH, NH₂; or cyclohexyl, which isoptionally substituted by one or two R^(3.2.1)R^(3.2.1)—NR^(3.2.1.1)R^(3.2.1.2) or a group selected from among

or a group selected from among

which is optionally substituted by one or more groups selected fromamong methyl, SO₂R^(3.2.1.1),

R^(3.2.1.1) denotes H, methyl or benzyl; R^(3.2.1.2) denotes H, methylor benzyl; or —C₁₋₆-alkyl, straight-chain or branched, which isoptionally substituted by one or two R^(3.2.2); R^(3.2.2) denotes C═CH₂,C≡CH, COOR^(3.2.2.1), CONR^(3.2.2.1)R^(3.2.2.2),NR^(3.2.2.1)R^(3.2.2.2), NHCOR^(3.2.2.1), CF₃, CN, OH, SO₂R^(3.2.2.1) ora group selected from among

or a group selected from among

which is optionally substituted by one or more groups selected fromamong Cl, methyl, CONR^(3.2.2.1)R^(3.2.2.2), OH; R^(3.2.2.1) denotes Hor methyl; R^(3.2.2.2) denotes H or methyl; or phenyl, which isoptionally substituted by one or two R^(3.2.3) R^(3.2.3) denotes a groupselected from among

R^(3.3) denotes H, C₁₋₆-alkyl, optionally substituted by one or moreR^(3.3.1); R^(3.3.1) denotes C₅₋₆-cycloalkyl, C₅₋₆-cycloalkenyl,OR^(3.3.1.1), NR^(3.3.1.1)R^(3.3.1.2), CONR^(3.3.1.1)R^(3.3.1.2),COOR^(3.3.1.1), NR^(3.3.1.1)COR^(3.3.1.2), SOR^(3.3.1.1),SO₂R^(3.3.1.1), C(NR^(3.3.1.1)R^(3.3.1.2))NR^(3.3.1.3),NR^(3.3.1.1)CONR^(3.3.1.2)R^(3.3.1.3), OH, CN, halogen or het which isoptionally substituted by one or more groups selected from among methyl,SO₂H, SO₂CH₃, SO₂CH₂phenyl,

R^(3.3.1.1), R^(3.3.1.2) and R^(3.3.1.3) denote a group selected fromamong C₁₋₄-alkyl, C₇₋₁₁-aralkyl, C₁₋₄-alkyl-hetaryl,COC₁₋₄-alkyl-hetaryl; R^(a) denotes H, methyl, ethyl, propyl, butyl,3-methyl-butyl, propenyl, cyclopropyl, cyclohexyl, CF₃, COR⁸, NR⁹R¹⁰,NO₂, OR⁸, SR¹¹, SOR¹¹, SO₂R¹¹ or a group selected from among

or a group selected from among

which may optionally be substituted by one or more Cl, or a groupselected from among

which may optionally be substituted by one or more CH₃, COCF₃, CH₂NH₂ orCH₂NHCOOR¹²; R⁸ denotes methyl, propyl, cyclopropyl, NH₂, furanyl orphenyl, optionally substituted by one or more chlorine; R⁹ denotes H,COOR¹² or piperidino, optionally substituted by one or more CH₃, or agroup selected from among methyl, ethyl and propyl, which may optionallybe substituted by one or more COOH, NMe₂ or 4-methylpiperazine; R¹⁰denotes H, methyl, COCH₃, C≡CH or CH₂C≡CH; R¹¹ denotes ethyl or propyl,optionally substituted by one or more NMe₂, R¹² denotes butyl R^(b)denotes R⁴, CH₂OR⁴, COR⁴, COOR⁴, CONR⁴R⁵, NH₂, NHCOOR⁴, NHCONR⁴R⁵ or OH;R⁴ denotes H, methyl, ethyl, 2-hydroxyethyl, propyl, C≡CH, CF₃, phenyl,

R⁵ denotes H, methyl or ethyl; R^(c) denotes NHR⁶ or a group selectedfrom among

wherein B denotes a bond, methylene, ethylene, propylene or butynylene;R⁶ denotes H, C₁₋₄-alkyl, aryl, optionally substituted by SO₂CH₃; R⁷denotes H, NR^(7.1)R^(7.2), OR^(7.2), SR^(7.2) or a group selected fromamong

R^(7.1) denotes H, methyl, ethyl, (CH₂)₂R^(7.1.1) or COObutyl; R^(7.2)denotes H, methyl or ethyl; R^(7.1.1) denotes NR^(7.1.1.1)R^(7.1.1.2),het or 1-imidazolyl, 2-(N-ethylpyrrolidine); R^(7.1.1.1) denotes H orC₁₋₆-alkyl; R^(7.1.1.2) denotes H or C₁₋₆-alkyl; or thepharmacologically acceptable salt thereof.
 6. The compound of formula 1according to claims 1; wherein R^(a) denotes phenyl or benzyl, in eachcase optionally substituted by one or more groups selected from amongR¹, R² and R³; or

R¹ denotes methyl, ethyl, propyl, butyl, CF₃, CH₂COOH, methoxy, F, Cl,Br, OH, CN, COR^(1.1), OCF₃, NO₂ or SO₂R^(1.1); R^(1.1) denotes OH,methyl, NH₂, NHMe, NMe₂,

R² denotes methyl, methoxy, F, Cl or Br; R³ denotes a group selectedfrom among

wherein n denotes 0 or 1; m denotes 0 or 1; o denotes 2; R^(3.1) denotesa group selected from among

or a group selected from among

which may optionally be substituted by one or more R^(3.1.1); R^(3.1.1)denotes methyl, ethyl, OH, CH₂OH, CH₂CH₂OH, CH₂NEt₂, COMe, COOH, CONH₂,NH₂,

R^(3.2) denotes a group selected from among

which is optionally substituted by one or more groups selected fromamong methyl, ethyl, cyclopentyl, OH, NH₂; or cyclohexyl, which isoptionally substituted by one or two R^(3.2.1) R^(3.2.1) denotes—NR^(3.2.1.1)R^(3.2.1.2) or a group selected from among

or a group selected from among

which is optionally substituted by one or more groups selected fromamong methyl, SO₂R^(3.2.1.1),

R^(3.2.1.1) denotes H, methyl or benzyl; R^(3.2.1.2) denotes H, methylor benzyl; or —C₁₋₆-alkyl, straight-chain or branched, which isoptionally substituted by one or two R^(3.2.2); R^(3.2.2) denotes C≡CH₂,C≡CH, COOR^(3.2.2.1), CONR^(3.2.2.1)R^(3.2.2.2),NR^(3.2.2.1)R^(3.2.2.2), NHCOR^(3.2.2.1), CF₃, CN, OH, SO₂R^(3.2.2.1) ora group selected from among

or a group selected from among

which is optionally substituted by one or more groups selected fromamong Cl, methyl, CONR^(3.2.2.1)R^(3.2.2.2), OH; R^(3.2.2.1) denotes Hor methyl; R^(3.2.2.2) denotes H or methyl; or phenyl, which isoptionally substituted by one or two R^(3.2.3) R^(3.2.3) denotes a groupselected from among

R^(3.3) denotes H, methyl or ethyl; R^(b) denotes R⁴, CH₂OR⁴, COR⁴,COOR⁴, CONR⁴R⁵, NH₂, NHCOOR⁴, NHCONR⁴R⁵ or OH; R⁴ denotes H, methyl,ethyl, 2-hydroxyethyl, propyl, C≡CH, CF₃, phenyl,

R⁵ denotes H, methyl or ethyl; R^(c) denotes NHR⁶ or a group selectedfrom among

wherein B denotes a bond, methylene, ethylene, propylene or butynylene;R⁶ denotes H, phenyl, optionally substituted by SO₂CH₃; R⁷ denotes H,NR^(7.1)R^(7.2), OR^(7.2), SR^(7.2) or a group selected from among

R^(7.1) denotes H, methyl, ethyl, (CH₂)₂R^(7.1.1) or COObutyl; R^(7.2)denotes H, methyl or ethyl; R^(7.1.1) denotes NMe₂ or 1-imidazolyl orthe pharmacologically acceptable salt thereof.
 7. The compound offormula 1 according to claim 1; wherein

R^(c) denotes a group wherein B denotes methylene, propylene; R⁷ denotesH, NR^(7.1)R^(7.2) or 1-imidazolyl; R^(7.1) denotes H or methyl; R^(7.2)denotes H or methyl; or the pharmacologically acceptable salt thereof.8. The compound of formula 1 according to claims 1; wherein R^(a)denotes phenyl, optionally substituted by one or more groups selectedfrom among R¹, R² and R³; or the pharmacologically acceptable saltthereof.
 9. The compound of formula 1 according to claim 1; whereinR^(a) denotes phenyl, optionally substituted by one or more groupsselected from among R¹ and R³; R¹ denotes methyl, ethyl, propyl, CF₃,methoxy, F, Cl or Br; R³ denotes a group

or the pharmacologically acceptable salt thereof.
 10. The compound offormula 1 according to claim 1; wherein R^(a) denotes phenyl, optionallysubstituted by one or more groups selected from among R¹ and R³; R¹denotes methyl, ethyl, propyl, CF₃, methoxy, F, Cl or Br; R³ denotes agroup

or the pharmacologically acceptable salt thereof.
 11. A compound offormula 1.1

wherein R^(a) denotes H, COR⁸, NR⁹R¹⁰, NO₂, OR⁸, SR¹¹, SOR¹¹, SO₂R¹¹,NHCO—C₁₋₆-alkyl-NH₂, or a group selected from among C₁₋₆-alkyl,C₂₋₆-alkenyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkenyl, C₁₋₆-haloalkyl, aryl,C₇₋₁₁-aralkyl, spiro, het, hetaryl and CH₂—O-aryl, which may optionallybe substituted; R⁸ denotes C₁₋₆-alkyl, C₃₋₆-cycloalkyl, NH₂, hetaryl oraryl, optionally substituted by one or more halogens or C₁₋₄-alkyl; R⁹denotes H, COOR¹², CONR¹² or C₁₋₆-alkyl, optionally substituted by oneor more COOH, N(C₁₋₆-alkyl)₂ or het, optionally substituted by one ormore C₁₋₆-alkyl; or R⁹ denotes het, optionally substituted by one ormore C₁₋₄-alkyl; R¹⁰ denotes H, C₁₋₆-alkyl, CO—C₁₋₆-alkyl orC₂₋₆-alkynyl; R¹¹ denotes C₁₋₆-alkyl, optionally substituted by one ormore N(C₁₋₄-alkyl)₂; R^(b) denotes R⁴, OR⁴, —CH₂OR⁴, COR⁴, COOR⁴,CONR⁴R⁵, NR⁴R⁵, NR⁵COR⁴, NR⁵COOR⁴, NR⁵CONR⁴R⁵, NR⁵SOR⁴ or NR⁵SO₂R⁴; R⁴,R⁵ denote H, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkylene-OH, C₂₋₆-alkenyl,C₇₋₁₁-aralkyl, C₂₋₄-alkenyl-aryl, C₂₋₄-alkynyl-aryl, C₁₋₄-alkyl-hetaryl,C₂₋₄-alkenyl-hetaryl, C₂₋₄-alkynyl-hetaryl, C₂₋₆-alkynyl, optionallysubstituted by Si(C₁₋₄-alkyl)₃, or R⁴ denotes a group selected fromamong aryl, het, hetaryl and optionally substituted by C₁₋₄-alkyl; or R⁴and R⁵ together form a five-, six- or seven-membered ring consisting ofcarbon atoms and optionally a heteroatom selected from among oxygen,nitrogen and sulphur; R^(c) denotes NHR⁶ or a group selected from among

wherein B denotes a bond, C₁₋₆-alkyl, C₂₋₆-alkenyl or C₂₋₆-alkynyl; R⁶denotes H or a group selected from among C₁₋₄-alkyl, C₂₋₄-alkenyl,C₂₋₄-alkynyl, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkenyl, het, aryl, hetaryloptionally substituted by one or more groups R^(6.1;) R^(6.1) denoteshalogen, CF₃, OH, CN, OMe, SO₂(C₁₋₄-alkyl); R⁷ denotes H, C₁₋₄-alkyl,C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₃₋₆-cycloalkyl, NR^(7.1)R^(7.2), OR^(7.2),SR^(7.2), hetaryl, het, optionally substituted by C₁₋₄-alkyl or CONH₂;R^(7.1) denotes H, C₁₋₆-alkyl, (CH₂)₂₋₄R^(7.1.1) or COObutyl; R^(7.2)denotes H, C₁₋₆-alkyl, optionally substituted by one or more OH;R^(7.1.1) denotes NR^(7.1.1.1)R^(7.1.1.2), het or 1-imidazolyl,2-(N-ethylpyrrolidine); R^(7.1.1.1) denotes H or C₁₋₆-alkyl; R^(7.1.1.2)denotes H or C₁₋₆-alkyl; or a pharmacologically acceptable salt thereof.12. The compound of formula 1.1 according to claim 11; wherein R^(a)denotes phenyl, optionally substituted by one or more groups selectedfrom among R¹, R² and R³; or

R¹ denotes methyl, ethyl, propyl, CF₃, CH₂COOH, methoxy, F, Cl, Br, CN,COR^(1.1) or SO₂R^(1.1); R^(1.1) denotes OH, methyl, NH₂, NHMe, NMe₂ or

R² denotes methyl, F, Cl or Br; R³ denotes a group selected from among

wherein n denotes 0 or 1; m denotes 0 or 1; o denotes 2; R^(3.1) denotesa group selected from among

or a group selected from among

which may optionally be substituted by one or more R^(31.1); R^(3.1.1)denotes methyl, OH, CH₂OH, CH₂CH₂OH, CH₂NEt₂, COMe, COOH, CONH₂,

R^(3.2) denotes a group selected from among

which is optionally substituted by one or more groups selected fromamong methyl, ethyl, cyclopentyl, OH, NH₂; or cyclohexyl, which isoptionally substituted by one or two R^(3.2.1) R^(3.2.1) denotes—NR^(3.2.1.1)R^(3.2.1.2) or a group selected from among

or a group selected from among

which is optionally substituted by one or more methyl groups R^(3.2.1.1)denotes H or methyl; R^(3.2.1.2) denotes H or methyl; or —C₁₋₆-alkyl,straight-chain or branched, which is optionally substituted by one ortwo R^(3.2.2); R^(3.2.2) denotes C═CH₂, C≡CH, COOR^(3.2.2.1),CONR^(3.2.2.1)R^(3.2.2.2), NR^(3.2.2.1)R^(3.2.2.2), CN, OH or a groupselected from among

or a group selected from among

which is optionally substituted by one or more groups selected fromamong methyl, CONR^(3.2.2.1)R^(3.2.2.2), OH; R^(3.2.2.1) denotes H ormethyl; R^(3.2.2.2) denotes H or methyl; or phenyl, which is optionallysubstituted by one or two R^(3.2.3) R^(3.2.3) denotes a group selectedfrom among

R^(3.3) denotes H, methyl or ethyl; R^(b) denotes R⁴, CH₂OCH₃, COR⁴,COOH, COOCH₃, CONR⁴R⁵, NH₂, NHCOOR⁴ or OH; R⁴ denotes H, methyl, propyl,C≡CH, phenyl,

R⁵ denotes H or methyl; R^(c) denotes a group

wherein B denotes methylene, propylene; R⁷ denotes H, NR^(7.1)R^(7.2) or1-imidazolyl; R^(7.1) denotes H or methyl; R^(7.2) denotes H or methyl;or the pharmacologically acceptable salt thereof.
 13. A compound offormula 1.2

wherein R^(a) denotes H, COR⁸, NR⁹R¹⁰, NO₂, OR⁸, SR¹¹, SOR¹¹, SO₂R¹¹,NHCO—C₁₋₆-alkyl-NH₂, or a group selected from among C₁₋₆-alkyl,C₂₋₆-alkenyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkenyl, C₁₋₆-haloalkyl, aryl,C₇₋₁₁-aralkyl, spiro, het, hetaryl and CH₂—O-aryl, which may optionallybe substituted; R⁸ denotes C₁₋₆-alkyl, C₃₋₆-cycloalkyl, NH₂, hetaryl oraryl, optionally substituted by one or more halogens or C₁₋₄-alkyl; R⁹denotes H, COOR¹², CONR¹² or C₁₋₆-alkyl, optionally substituted by oneor more COOH, N(C₁₋₆-alkyl)₂ or het, optionally substituted by one ormore C₁₋₆-alkyl; or R⁹ denotes het, optionally substituted by one ormore C₁₋₄-alkyl; R¹⁰ denotes H, C₁₋₆-alkyl, CO—C₁₋₆-alkyl orC₂₋₆-alkynyl; R¹¹ denotes C₁₋₆-alkyl, optionally substituted by one ormore N(C₁₋₄-alkyl)₂; R^(b) denotes R⁴, OR⁴, —CH₂OR⁴, COR⁴, COOR⁴,CONR⁴R⁵, NR⁴R⁵, NR⁵COR⁴, NR⁵COOR⁴, NR⁵, CONR⁴R⁵, NR⁵SOR⁴ or NR⁵SO₂R⁴;R⁴, R⁵ denote H, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkylene-OH,C₂₋₆-alkenyl, C₇₋₁₁-aralkyl, C₂₋₄-alkenyl-aryl, C₂₋₄-alkynyl-aryl,C₁₋₄-alkyl-hetaryl, C₂₋₄-alkenyl-hetaryl, C₂₋₄-alkynyl-hetaryl,C₂₋₆-alkynyl, optionally substituted by Si(C₁₋₄-alkyl)₃, or R⁴ denotes agroup selected from among aryl, het, hetaryl and optionally substitutedby C₁₋₄-alkyl; or R⁴ and R⁵ together form a five-, six- orseven-membered ring consisting of carbon atoms and optionally aheteroatom selected from among oxygen, nitrogen and sulphur; R^(c)denotes NHR⁶ or a group selected from among

wherein B denotes a bond, C₁₋₆-alkyl, C₂₋₆-alkenyl or C₂₋₆-alkynyl; R⁶denotes H or a group selected from among C₁₋₄-alkyl, C₂₋₄-alkenyl,C₂₋₄-alkynyl, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkenyl, het, aryl, hetaryloptionally substituted by one or more groups R^(6.1); R^(6.1) denoteshalogen, CF₃, OH, CN, OMe, SO₂(C₁₋₄-alkyl); R⁷ denotes H, C₁₋₄-alkyl,C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₃₋₆-cycloalkyl, NR^(7.1)R^(7.2), OR^(7.2),SR^(7.2), hetaryl, het, optionally substituted by C₁₋₄-alkyl or CONH₂;R^(7.1) denotes H, C₁₋₆-alkyl, (CH₂)₂₋₄R^(7.1.1) or COObutyl; R^(7.2)denotes H, C₁₋₆-alkyl, optionally substituted by one or more OH;R^(7.1.1) denotes NR^(7.1.1.1)R^(7.1.1.2), het or 1-imidazolyl,2-(N-ethylpyrrolidine); R^(7.1.1.1) denotes H or C₁₋₆-alkyl; R^(7.1.1.2)denotes H or C₁₋₆-alkyl; or a pharmacologically acceptable salt thereof14. The compound of formula 1.2 according to claim 13; wherein R^(a)denotes phenyl, optionally substituted by one or more groups selectedfrom among R¹ and R²; R¹ denotes methyl, ethyl, propyl, CF₃, F, Cl,COR^(1.1) or SO₂R^(1.1); R^(1.1) denotes methyl; R² denotes methyl, F orCl; R^(b) denotes R⁴; R⁴ denotes H; R^(c) denotes NHR⁶ or a group

wherein B denotes a bond, methylene, ethylene or propylene; R⁶ denotesH; R⁷ denotes H or NR^(7.1)R^(7.2),

R^(7.1) denotes H, methyl, ethyl, (CH₂)₂R^(7.1.1) or COObutyl; R^(7.2)denotes H, methyl or ethyl; R^(7.1.1) denotes NMe₂ or 1-imidazolyl orthe pharmacologically acceptable salt thereof.
 15. A compound of formula1.3

wherein R^(a) denotes H, COR⁸, NR⁹R¹⁰, NO₂, OR⁸, SR¹¹, SOR¹¹, SO₂R¹¹,NHCO—C₁₋₆-alkyl-NH₂, or a group selected from among C₁₋₆-alkyl,C₂₋₆-alkenyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkenyl, C₁₋₆-haloalkyl, aryl,C₇₋₁₁-aralkyl, spiro, het, hetaryl and CH₂—O-aryl, which may optionallybe substituted; R⁸ denotes C₁₋₆-alkyl, C₃₋₆-cycloalkyl, NH₂, hetaryl oraryl, optionally substituted by one or more halogens or C₁₋₄-alkyl; R⁹denotes H, COOR¹², CONR¹² or C₁₋₆-alkyl, optionally substituted by oneor more COOH, N(C₁₋₆-alkyl)₂ or het, optionally substituted by one ormore C₁₋₆-alkyl; or R⁹ denotes het, optionally substituted by one ormore C₁₋₄-alkyl; R¹⁰ denotes H, C₁₋₆-alkyl, CO—C₁₋₆-alkyl orC₂₋₆-alkynyl; R¹¹ denotes C₁₋₆-alkyl, optionally substituted by one ormore N(C₁₋₄-alkyl)₂; R^(b) denotes R⁴, OR⁴, —CH₂OR⁴, COR⁴, COOR⁴,CONR⁴R⁵, NR⁴R⁵, NR⁵COR⁴, NR⁵COOR⁴, NR⁵CONR⁴R⁵, NR⁵SOR⁴ or NR⁵SO₂R⁴; R⁴,R⁵ denote H, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkylene-OH, C₂₋₆-alkenyl,C₇₋₁₁-aralkyl, C₂₋₄-alkenyl-aryl, C₂₋₄-alkynyl-aryl, C₁₋₄-alkyl-hetaryl,C₂₋₄-alkenyl-hetaryl, C₂₋₄-alkynyl-hetaryl, C₂₋₆-alkynyl, optionallysubstituted by Si(C₁₋₄-alkyl)₃, or R⁴ denotes a group selected fromamong aryl, het, hetaryl and optionally substituted by C₁₋₄-alkyl; or R⁴and R⁵ together form a five-, six- or seven-membered ring consisting ofcarbon atoms and optionally a heteroatom selected from among oxygen,nitrogen and sulphur; R^(c) denotes NHR⁶ or a group selected from among

wherein B denotes a bond, C₁₋₆-alkyl, C₂₋₆-alkenyl or C₂₋₆-alkynyl; R⁶denotes H or a group selected from among C₁₋₄-alkyl, C₂₋₄-alkenyl,C₂₋₄-alkynyl, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkenyl, het, aryl, hetaryloptionally substituted by one or more groups R^(6.1); R^(6.1) denoteshalogen, CF₃, OH, CN, OMe, SO₂(C₁₋₄-alkyl); R⁷ denotes H, C₁₋₄-alkyl,C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₃₋₆-cycloalkyl, NR^(7.1)R^(7.2), OR^(7.2),SR^(7.2), hetaryl, het, optionally substituted by C₁₋₄-alkyl or CONH₂;R^(7.1) denotes H, C₁₋₆-alkyl, (CH₂)₂₋₄R^(7.1.1) or COObutyl; R^(7.2)denotes H, C₁₋₆-alkyl, optionally substituted by one or more OH;R^(7.1.1) denotes NR^(7.1.1.1)R^(7.1.1.2), het or 1-imidazolyl,2-(N-ethylpyrrolidine); R^(7.1.1.1) denotes H or C₁₋₆-alkyl; R^(7.1.1.2)denotes H or C₁₋₆-alkyl; or a pharmacologically acceptable salt thereof.16. The compound of formula 1.3 according to one of claim 15; whereinR^(a) denotes phenyl, optionally substituted by one or more groupsselected from among R¹ and R²; or

R¹ denotes methyl, methoxy, Cl, OH or COR^(1.1); R^(1.1) denotes NH₂,NHMe or NMe₂; R² denotes methoxy or Cl; R^(b) denotes R⁴ or OH; R⁴denotes H;

R^(c) denotes NHR⁶ or a group wherein B denotes a bond, methylene,ethylene or propylene; R⁶ denotes H; R⁷ denotes H, NR^(7.1)R^(7.2) or agroup selected from among

R^(7.1) denotes H, methyl or (CH₂)₂R^(7.1.1); R^(7.2) denotes H, methylor ethyl; R^(7.1.1) denotes NMe₂; or the pharmacologically acceptablesalt thereof.
 17. A compound of formula 1.4

wherein R^(a) denotes H, COR⁸, NR⁹R¹⁰, NO₂, OR⁸, SR¹¹, SOR¹¹, SO₂R¹¹,NHCO—C₁₋₆-alkyl-NH₂, or a group selected from among C₁₋₆-alkyl,C₂₋₆-alkenyl, C₃₋₈-cycloalkyl, C₃₋₈-cycloalkenyl, C₁₋₆-haloalkyl, aryl,C₇₋₁₁-aralkyl, spiro, het, hetaryl and CH₂—O-aryl, which may optionallybe substituted; R⁸ denotes C₁₋₆-alkyl, C₃₋₆-cycloalkyl, NH₂, hetaryl oraryl, optionally substituted by one or more halogens or C₁₋₄-alkyl; R⁹denotes H, COOR¹², CONR¹² or C₁₋₆-alkyl, optionally substituted by oneor more COOH, N(C₁₋₆-alkyl)₂ or het, optionally substituted by one ormore C₁₋₆-alkyl; or R⁹ denotes het, optionally substituted by one ormore C₁₋₄-alkyl; R¹⁰ denotes H, C₁₋₆-alkyl, CO—C₁₋₆-alkyl orC₂₋₆-alkynyl; R¹¹ denotes C₁₋₆-alkyl, optionally substituted by one ormore N(C₁₋₄-alkyl)₂; R^(b) denotes R⁴, OR⁴, —CH₂OR⁴, COR⁴, COOR⁴,CONR⁴R⁵, NR⁴R⁵, NR⁵COR⁴, NR⁵COOR⁴, NR⁵, CONR⁴R⁵, NR⁵SOR⁴ or NR⁵SO₂R⁴;R⁴, R⁵ denote H, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₁₋₆-alkylene-OH,C₂₋₆-alkenyl, C₇₋₁₁-aralkyl, C₂₋₄-alkenyl-aryl, C₂₋₄-alkynyl-aryl,C₁₋₄-alkyl-hetaryl, C₂₋₄-alkenyl-hetaryl, C₂₋₄-alkynyl-hetaryl,C₂₋₆-alkynyl, optionally substituted by Si(C₁₋₄-alkyl)₃, or R⁴ denotes agroup selected from among aryl, het, hetaryl and optionally substitutedby C₁₋₄-alkyl; or R⁴ and R⁵ together form a five-, six- orseven-membered ring consisting of carbon atoms and optionally aheteroatom selected from among oxygen, nitrogen and sulphur; R^(c)denotes NHR⁶ or a group selected from among

wherein B denotes a bond, C₁₋₆-alkyl, C₂₋₆-alkenyl or C₂₋₆-alkynyl; R⁶denotes H or a group selected from among C₁₋₄-alkyl, C₂₋₄-alkenyl,C₂₋₄-alkynyl, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkenyl, het, aryl, hetaryloptionally substituted by one or more groups R^(6.1;) R^(6.1) denoteshalogen, CF₃, OH, CN, OMe, SO₂(C₁₋₄-alkyl); R⁷ denotes H, C₁₋₄-alkyl,C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₃₋₆-cycloalkyl, NR^(7.1)R^(7.2), OR^(7.2),SR^(7.2), hetaryl, het, optionally substituted by C₁₋₄-alkyl or CONH₂;R^(7.1) denotes H, C₁₋₆-alkyl, (CH₂)₂₋₄R^(7.1.1) or COObutyl; R^(7.2)denotes H, C₁₋₆-alkyl, optionally substituted by one or more OH;R^(7.1.1) denotes NR^(7.1.1.1)R^(7.1.1.2), het or 1-imidazolyl,2-(N-ethylpyrrolidine); R^(7.1.1.1) denotes H or C₁₋₆-alkyl; R^(7.1.1.2)denotes H or C₁₋₆-alkyl; or a pharmacologically acceptable salt thereof.18. The compound of formula 1.4 according to claim 17; wherein R^(a)denotes phenyl, optionally substituted by one or more groups selectedfrom among R¹ and R³; or R¹ denotes methyl, F, Cl or Br; R³ denotes agroup selected from among

wherein m denotes 0; R^(3.2) denotes a group

which is optionally substituted by a group selected from among methyland cyclopentyl; cyclohexyl, which is optionally substituted by aR^(3.2.1) R^(3.2.1) denotes a group

R^(3.3) denotes H; R^(b) denotes R⁴; R⁴ denotes a group selected fromamong

R^(c) denotes a group

wherein B denotes methylene; R⁷ denotes H; or the pharmacologicallyacceptable salt thereof.
 19. The compound of formula 1 according toclaim 1; wherein R^(a) denotes H, C₁₋₆-alkyl, C₂₋₆-alkenyl,C₃₋₆-cycloalkyl, C₃₋₆-cycloalkenyl, CF₃, COR⁸, NR⁹R¹⁰, NO₂, S(O)_(n)R¹¹,spiro, NHCO—C₁₋₆-alkyl-NH₂ or a group selected from among C₇₋₁₁-aralkyland CH₂O-aryl, which may optionally be substituted by one or more Cl; ora group selected from among het, which may optionally be substituted byone or more C₁₋₄-alkyl, COCF₃, CH₂NH₂ or CH₂NHCOOR¹²; R⁸ denotesC₁₋₄-alkyl, C₃₋₆-cycloalkyl, NH₂, hetaryl, aryl, optionally substitutedby one or more chlorine; R⁹ denotes H, COOR¹² or het, optionallysubstituted by one or more C₁₋₄-alkyl, or a group selected from amongC₁₋₄-alkyl, which may optionally be substituted by one or more COOH,N(C₁₋₄-alkyl)₂ or 4-methylpiperazine; R¹⁰ denotes H, C₁₋₄-alkyl,C₂₋₄-alkynyl or COCH₃; R¹¹ denotes C₁₋₄-alkyl, optionally substituted byone or more N(C₁₋₄-alkyl)₂, R¹² denotes C₁₋₄-alkyl; n denotes 0 or 2;R^(b) denotes H, OH or COOEt; R^(c) denotes NH₂ or NHCOR¹³; R¹³ denotesC₁₋₄-alkyl, or NR^(13.1)R^(13.2), R^(13.1) denotes H or C₁₋₄-alkyl;R^(13.2) denotes H or C₁₋₄-alkyl; or the pharmacologically acceptablesalt thereof.
 20. The compound of formula 1 according to claim 19;wherein R^(a) denotes H, methyl, ethyl, propyl, butyl, 3-methyl-butyl,propenyl, cyclopropyl, cyclohexyl, CF₃, COR⁸, NR⁹R¹⁰, NO₂, S(O)_(n)R¹¹,or a group selected from among

or a group selected from among

which may optionally be substituted by one or more Cl; or a groupselected from among

which may optionally be substituted by one or more CH₃, COCF₃, CH₂NH₂ orCH₂NHCOOR¹² R⁸ denotes methyl, propyl, cyclopropyl, NH₂, furanyl orphenyl, optionally substituted by one or more chlorine; R⁹ denotes H,COOR¹² or piperidino, optionally substituted by one or more CH₃, or agroup selected from among methyl, ethyl and propyl, which may optionallybe substituted by one or more COOH, NMe₂ or 4-methylpiperazine; R¹⁰denotes H, methyl, COCH₃, C≡CH or CH₂C≡CH; R¹¹ denotes ethyl or propyl,optionally substituted by one or more NMe₂, R¹² denotes butyl R^(b)denotes H, OH or COOEt; R^(c) denotes NH₂ or NHCOR¹³; R¹³ denotes methylor NR^(13.1)R^(13.2), R^(13.1) denotes H or methyl; R^(13.2) denotes Hor methyl. or the pharmacologically acceptable salt thereof.
 21. Apharmaceutical composition of matter comprising a compound according toclaim 1 and one or more pharmaceutically acceptable excipients orcarriers.
 22. A method of treating a warm blooded animal for a diseasewhose pathology involves an activity of PI3-kinases, which comprisesadministering to the animal a therapeutically effective amount of acompound according to claim
 1. 23. The method according to claim 22,characterised in that the disease is selected from inflammatory andallergic diseases of the airways.
 24. The method according to claim 23,characterised in that the disease is selected from among chronicbronchitis, acute bronchitis, bronchitis caused by bacterial or viralinfection or fungi or helminths, allergic bronchitis, toxic bronchitis,chronic obstructive bronchitis (COPD), asthma (intrinsic or allergic),pediatric asthma, bronchiectasis, allergic alveolitis, allergic ornon-allergic rhinitis, chronic sinusitis, cystic fibrosis ormucoviscidosis, alpha-1-antitrypsin deficiency, cough, pulmonaryemphysema, interstitial lung diseases, alveolitis, hyperreactiveairways, nasal polyps, pulmonary oedema, pneumonitis of differentorigins, e.g. radiation-induced or caused by aspiration, or infectiouspneumonitis, collagenoses such as lupus eryth, systemic sclerodermy,sarcoidosis and Boeck's disease.
 25. The method according to claim 22,characterised in that the disease relates to inflammatory and allergicdiseases of the skin.
 26. The method according to claim 22,characterised in that the disease is selected from among psoriasis,contact dermatitis, atopic dermatitis, alopecia areata (circular hairloss), erythema exsudativum multiforme (Stevens-Johnson Syndrome),dermatitis herpetiformis, sclerodermy, vitiligo, nettle rash(urticaria), lupus erythematodes, follicular and surface pyodermy,endogenous and exogenous acne, acne rosacea and other inflammatory andallergic or proliferative skin diseases.
 27. The method according toclaim 22, characterised in that the disease relates to inflammation ofthe eye.
 28. The method according to claim 27, characterised in that itrelates to a disease selected from among inflammation of the conjunctiva(conjunctivitis) of various kinds, such as e.g. caused by infection withfungi or bacteria, allergic conjunctivitis, irritable conjunctivitis,drug-induced conjunctivitis, keratitis and uveitis.
 29. The methodaccording to claim 22, characterised in that the disease relates todiseases of the nasal mucosa.
 30. The method according to claim 29,characterised in that the disease is selected from among allergicrhinitis, allergic sinusitis and nasal polyps.
 31. The method accordingto claim 22, characterised in that the disease relates to inflammatoryor allergic conditions involving autoimmune reactions.
 32. The methodaccording to claim 31, characterised in that the disease is selectedfrom among Crohn's disease, ulcerative colitis, systemic lupuserythematodes, chronic hepatitis, multiple sclerosis, rheumatoidarthritis, psoriatic arthritis, osteoarthritis, and rheumatoidspondylitis.
 33. The method according to claim 22, characterised in thatthe disease relates to kidney inflammations.
 34. The method according toclaim 33, characterised in that the disease is selected from amongglomerulonephritis, interstitial nephritis and idiopathic nephroticsyndrome.